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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nutrition 36 (1997), S. 23-27 
    ISSN: 1436-6215
    Keywords: Vitamin E ; Fleisch ; Fettgewebe ; Leber ; Eigelb ; Vitamin E ; meat ; adipose tissue ; liver ; egg yolk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Summary The α-tocopherol content of different meat cuts was examined. Chicken thigh had the highest vitamin E content, followed by chicken breast and pork shoulder (p〈0.05). The lowest concentrations were found in longissimus dorsi muscle from pork, beef, veal and in beef shoulder. Considering the average daily lean meat consumption (105 g) in Switzerland, recommendation for daily vitamin E intake was met to 3 %. Supplementation of 200 mg α-tocopherol acetate/kg feed to pigs and laying hens significantly increased the α-tocopherol content in all examined products. The α-tocopherol accumulation differed according to the following ranking: egg yolk 〉 liver 〉 adipose tissue 〉 musculus longissimus dorsi. The α-tocopherol:energy ratios were 28.8, 7.3, 0.9 and 1.2 mg/MJ for egg yolk, liver, adipose tissue and longissimus dorsi muscle of the vitamin E supplemented groups, respectively. The results showed that meat, with the exception of chicken thigh, is not an important supplier of vitamin E, not even from animals fed a vitamin E enriched diet. Egg yolk became a good source of vitamin E for human nutrition by dietary modification.
    Notes: Zusammenfassung In der vorliegenden Studie wurde der α-Tocopherolgehalt verschiedener Fleischstücke untersucht. Hähnchenschenkel hatte den höchsten α-Tocopherolgehalt, gefolgt von Hähnchenbrust und Schweineschulter (p〈0.05). Die niedrigsten Konzentrationen wurden im Musculus longissimus dorsi vom Schwein, Rind, Kalb und in der Rindsschulter nachgewiesen. Mit dem durchschnittlichen, täglichen Verzehr an magerem Fleisch (105 g) in der Schweiz wurden die Empfehlungen für die tägliche Vitamin E-Zufuhr zu 3 % gedeckt. Die Supplementierung des Schweine- und Legehennenfutters mit 200 mg α-Tocopherolacetat/kg führte zu einem signifikanten Anstieg des α-Tocopherolgehaltes in allen untersuchten Produkten. Die α-Tocopherolakkumulierung unterschied sich gemäß folgender Rangordnung: Eigelb 〉 Leber 〉 Fettgewebe 〉Musculus longissimus dorsi. Die Nährstoffdichten betrugen 28.8, 7.3, 0.9 und 1.2 mg α-Tocopherol/MJ für Eigelb, Leber, Fettgewebe und Musculus longissimus dorsi der jeweiligen mit Vitamin E supplementierten Gruppe. Diese Ergebnisse zeigen, daß Fleisch, mit Ausnahme des Hähnchenschenkels, von Tieren mit supplementierten Diäten kein bedeutender Vitamin E-Lieferant ist. Hingegen wurde Eigelb durch fütterungsbedingte Modifikation zu einer guten Vitamin E-Quelle.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    BioMetals 10 (1997), S. 351-355 
    ISSN: 1572-8773
    Keywords: heart ; liver ; maghemite ; magnetite ; spleen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Isothermal remanent magnetization (IRM) acquisition and alternating field (A.F.) demagnetization analyses were performed on human heart, spleen and liver samples resected from cadavers. The magnetic properties of the samples were measured both at 77K and at 273K. A.F. demagnetization was performed at 273K. Results from the analyses of the tissue indicate the presence of ferromagnetic, fine-grained, magnetically interacting particles which, due primarily to magnetic properties, are thought to be magnetite and/or maghemite. The presence of superparamagnetic particles can be inferred from the increase in saturation IRM values when measured at 77K compared with measurements at 273K and the decay of remanent magnetization upon warming from 77K. The concentration of magnetic material (assuming it is magnetite or maghemite) in the samples varies from 13.7 ng g-1 to 343 ng g-1, with the heart tissue generally having the highest concentration. The presence of magnetic material in these organs may have implications for the function of biogenic magnetite in the human body.
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  • 3
    ISSN: 1572-8773
    Keywords: energy dispersive X-ray fluorescence ; liver ; lead toxicity ; inter-elemental effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Energy dispersive X-ray fluorescence technique was employed to study the interactions of lead (50 and 100 mg/kg body wt) with K, Fe, Cu, Zn, Br and Rb in rat liver. Lead was administered orally to rats daily for dosage periods of 1 and 4 months (short and long terms). Hepatic Fe levels were found to increase significantly with the supplementation of low and high doses of lead for both the treatment periods, although the increase was more pronounced following long-term treatment. The levels of hepatic K, Cu and Br were seen to decrease significantly over both time intervals. Moreover, hepatic Rb contents were lowered with the short-term supplementation of low doses of lead. In contrast, Rb and Zn levels were increased when lead was administered for the longer period at both dose levels.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 40 (1984), S. 986-988 
    ISSN: 1420-9071
    Keywords: Chick embryos ; liver ; chick ; chick ; liver ; nuclear size ; polyploidy ; multinuclearity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Increase in nuclear size in liver has been used as an index of polyploidy. It has long been considered that the occurrence of polyploidy and multinuclearity are characteristics of mammalian liver. The present study shows the occurrence of these phenomena in the liver of birds, so these features are not confined to mammals. 3 classes of nuclear size groups have been identified. The simultaneous occurrence of polyploidy and binuclearity indicates some sort of interrelationship between them.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nutrition 34 (1995), S. 220-223 
    ISSN: 1436-6215
    Keywords: Ascorbic acid ; glutathioneperoxidase ; lipid peroxides ; liver ; Ascorbinsäure ; Glutathion-Peroxidase ; Lipidperoxiden ; Leber
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Verschiedene Werte an antioxidativem Potential, erzeugt mit Hilfe verschiedener Konzentrationsstufen an Ascorbinsäure (1, 10, 100 mg/Tier/Tag) führten zu Veränderungen in der GSH-Px Aktivität und der Menge den Lipidperoxiden in der Leber von Meerschweinchen. Die Gruppe mit der kleinsten Dosierung (1 mg) von Ascorbinsäure hatte die niedrigste GSH-Px Aktivität und den höchsten Anteil an Lipidperoxiden. Die zwei anderen Gruppen zeigten eine Erhöhung der GSH-Px Aktivität und Senkung von Lipidperoxiden auf. Es bestand kein Unterschied zwischen den Gruppen mit der Dosis von 10 und 100 mg Ascorbinsäure.
    Notes: Summary Differing antioxidant potentials created by graded ascorbic acid supplementation (1, 10, 100 mg per animal daily) evoked changes in the level of glutathione peroxidase activity and lipid peroxides in the liver of female guinea pigs. The group with the lowest ascorbic acid intake (1 mg) had the lowest activity of glutathione peroxidase and the highest level of lipid peroxides. The two other groups (10 and 100 mg) showed enhancement of glutathione peroxidase activity and decline in lipid peroxides. There was no difference between the groups with 10 and 100 mg ascorbic acid intake.
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  • 6
    ISSN: 1436-6215
    Keywords: Riboflavin ; Milch ; Leber ; Restkörper ; Laktation ; Ratte ; Riboflavin ; milk ; liver ; carcass ; lactation ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Summary The present study investigated the effect of various dietary riboflavin supplementations (0 to 4 000 mg/kg) during lactation on riboflavin concentrations of liver, carcass (bled body without intestine and liver), and milk in the rat. The experiment was conducted until the 14th day of lactation; milk samples were drawn on the 7th and 13th day of lactation. Riboflavin concentrations of milk raised continuously with increasing riboflavin supplementation; in the range between 0 and 10 mg/kg riboflavin supplementation, there was a linear relationship, and in the range between 12 and 4 000 mg/kg there was a logarithmic relationship between riboflavin supplementation and riboflavin concentration in the milk. Maximum riboflavin concentration of milk obtained by supplementation with 4 000 mg/kg was twelve-fold higher than without riboflavin supplementation. For riboflavin supplementation up to 12 mg/kg, riboflavin concentrations in milk on the 7th day of lactation and that on the 13th day of lactation were not different. In contrast, in rats fed diets with higher riboflavin supplementation, riboflavin concentrations were higher by 25 % in average in milk on the 13th day of lactation than in milk on the 7th day of lactation. Contrary to the milk, riboflavin concentrations in liver and carcass exhibited a saturation, which was achieved at a supplementation of 6 mg/kg (liver) and 10 mg/kg (carcass), respectively. Maximum riboflavin concentrations obtained at a supplementation of 4 000 mg/kg were 1.9- and 2.3-fold higher for liver and carcass, respectively, than concentrations obtained without riboflavin supplementation. The dose-response relationship using riboflavin concentrations of liver and carcass as response factors indicates a riboflavin requirement of 8 to 9 mg/kg for lactating rats fed a semisynthetic diet with 17.4 MJ ME/kg dry matter and 20.8 % protein in dry matter.
    Notes: Zusammenfassung In der vorliegenden Arbeit wurde der Einfluß unterschiedlicher Riboflavinzulagen zum Futter (0 bis 4 000 mg/kg) während der Laktation auf die Riboflavinkonzentrationen in Leber, Restkörper (ausgebluteter Gesamtkörper ohne Magen-Darm-Trakt und Leber) und Milch von Ratten untersucht. Der Versuch dauerte bis zum 14. Laktationstag; Milchproben wurden am 7. und am 13. Laktationstag gewonnen. Die Riboflavinkonzentration der Milch erhöhte sich mit steigender Zulage stetig, wobei im Bereich zwischen 0 und 10 mg Riboflavinzulage/kg Futter eine lineare und im Bereich zwischen 12 und 4 000 mg/kg eine logarithmische Funktion vorlag. Die maximale Riboflavinkonzentration in der Milch bei einer Zulage von 4 000 mg/kg war dabei etwa zwölfmal so hoch wie bei fehlender Zulage. Bei Riboflavinzulagen bis 12 mg/kg unterschieden sich die Riboflavinkonzentrationen der Milch am 7. und 13. Laktationstag nicht. Bei den höheren Zulagen waren die Konzentrationen der Milch am 13. Laktationstag im Mittel um 25 % höher als am 7. Laktationstag. Im Gegensatz zur Milch zeigte sich in Leber und Restkörper eine Sättigung der Riboflavinkonzentrationen, die bei einer Riboflavinzulage von 6 mg/kg (Leber) bzw. 10 mg/kg (Restkörper) erreicht war. Die maximalen Riboflavinkonzentrationen bei Zulagen von 4 000 mg/kg waren dabei 1,9 (Leber) bzw. 2,3 (Restkörper) mal so hoch wie bei fehlender Riboflavinzulage. Diese Befunde sprechen für eine ausgeprägte homöostatische Kontrolle der Riboflavinkonzentrationen im Organismus. Anhand von Dosis-Wirkungsbeziehungen mit den Riboflavinkonzentrationen in Leber und Restkörper als Wirkungskriterien leitete sich bei Verwendung des halbsynthetischen Futters (17,4 MJ ME/kg Trockenmasse (T), 20,8 % Rohprotein in T) ein Riboflavinbedarf von 8 bis 9 mg/kg Futter für die laktierende Ratte ab.
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  • 7
    ISSN: 1436-6215
    Keywords: Environmental temperature ; energy expenditure ; ouabain-sensitive respiration ; duodenal mucosa ; liver ; rats ; Umgebungstemperatur ; Energieumsatz ; Quabain-sensitive Respiration ; Duodenalmukosa ; Leber ; Ratten
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Die Wirkung der Umgebungstemperatur (18°C oder 28°C) und des Fasergehalts in der Diät (g je kg Trockensubstanz (TS) niedrig - 68, mittel - 110, hoch - 157) oder des Proteingehalts (g je kg TS niedrig - 91, mittel- 171, hoch - 262) auf den Verdauungstrakt, die Darmmasse, den Energieumsatz und auf die mit der Na+, K+-ATPase-Aktivität zusammenhängenden Respiration von Duodenalmukosa und Leber wurde bei 72 Wistar-Ratten in wiederholten Experimenten untersucht. Der Gesamte und Quabain-sensitive (ein Maß der Na+, K+-ATPase Aktivität) O2-Verbrauch der Gewebe wurde in vitro polarographisch ermittelt (YSI-biologische Sauerstoff-Erfassung nach dem Clark-Meßprinzip). Die Wärmeproduktion (WP) intakter Tiere wurde über Respirationskammern mit offenem Gasaustausch erfaßt. Die bei 18°C gehaltenen Ratten wiesen im Vergleich zu 28°C eine höhere Darmmasse auf. Die Masse an leerem Dünndarm, Caecum und Colon stieg mit ansteigendem Fasergehalt in der Diät (P〈0.05). Die WP als Korrelat der umsetzbaren Energie war nur im 1. Experiment höher (P〈0.05) bei 18°C als bei 28°C. Bei niedriger Proteinstufe war die WP signifikant höher (P 0.05) als bei den anderen Stufen. Verglichen mit 28°C erzeugte 18°C einen ansteigenden Gesamt- und Quabain-sensitiven O2-Verbrauch in der Duodenalmukosa. Die Leber reagierte nicht auf Temperaturunterschiede. Jedoch war ihr Quabain-sensitiver O2-Verbrauch bei niedrigem Proteingehalt in der Nahrung höher (P〈0.05) als bei den anderen Varianten. Bei niedrigem Fasergehalt war der gesamte und Quabain-sensitive O2-Verbrauch der Duodenalmukosa höher als bei den anderen Fasergehaltsvarianten. Die In-vitro-Ergebnisse stimmten mit der WP und dem O2-Verbrauch intakter Tiere überein.
    Notes: Summary Seventy two Wistar rats were used in two repeat studies to investigate the effect of environmental temperature (18°C or 28°C) and increasing levels of dietary fibre (low, 68 g/kg DM; medium 110 g/kg DM; high, 157 g/kg DM) or protein (low, 91 g/kg DM; medium, 171 g/kg DM; high, 262 g/kg DM) on digestive tract, visceral organ size, energy metabolism, and respiration attributable to Na+,K+-ATPase activity in duodenal mucosa and liver. Total and ouabain-sensitive (a measure of Na+,K+-ATPase activity) O2 consumptionin vitro of tissues were measured polarographically using a Clark-style YSI biological O2 monitor. Whole body heat production (in vivo) was measured using open-circuit respiration chambers. The weight of the visceral organs was higher in rats housed at 18°C than at 28°C. The empty weight of the small intestine, caecum, and colon increased as the level of dietary fibre increased (P 0.05). Heat production as a proportion of metabolizable energy was higher (P〈0.05) at 18°C than at 28°C in the first experiment but this difference was not significant in the second experiment. Rats fed the low protein diet had significantly higher (P〉0.05) heat production than those fed medium or high protein diets. Compared to 28°C, environmental temperature of 18°C caused an increased total and ouabain-sensitive O2 consumption in duodenal mucosa. There was no significant effect of environmental temperature on total and ouabain-sensitive O2 consumption in the liver. However, ouabain-sensitive O2 consumption in liver was significantly higher (P 0.05) when rats were fed a low protein diet compared to the medium or high protein diet. Total and ouabain-sensitive O2 consumption increased in duodenal mucosa of rats fed low level of dietary fibre compared to the medium or high dietary fibre diets. Thein vitro results corresponded with the whole animal energy expenditure and O2 consumptionin vivo.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 51 (1995), S. 589-591 
    ISSN: 1420-9071
    Keywords: Oyster mushroom (Pleurotus ostreatus) ; cholesterol ; serum ; lipoproteins ; liver ; HMG-CoA reductase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The effect of dried oyster mushroom (Pleurotus ostreatus) on cholesterol (C) content in serum, in lipoproteins and in liver, and on the activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in liver microsomes, was studied in male rats (strain Wistar, initial body weight 75 g) fed on low-cholesterol (9 mg/100 g) and high-cholesterol (0.3%) diets. Addition of 5% oyster mushroom to both diets reduced significantly the C-content in serum (by 30%), in very-low- and low-density lipoproteins (in a 1∶1 ratio to the decrease of total serum C) and in liver (by 50%), as well as the activity of HMG-CoA reductase (by more than 30%).
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  • 9
    Electronic Resource
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    Springer
    European journal of clinical pharmacology 47 (1995), S. 507-511 
    ISSN: 1432-1041
    Keywords: Methotrexate ; Juvenile rheumatoid arthritis ; pharmacokinetics ; age dependence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5–16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg·kg−1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 47 (1995), S. 525-530 
    ISSN: 1432-1041
    Keywords: Antipyrine disposition ; Obesity ; pharmacokinetics ; oxidative metabolism ; weight reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg · m−2 and 181vs 106 % respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss. Antipyrine apparent volume of distribution (V) and elimination half-life (t 1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t 1/2 15.5 vs 12.0 h respectively), but its clearance rate (CLo) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l · kg−1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t 1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CLo. We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t 1/2 whereas its CLo is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.
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  • 11
    ISSN: 1432-1041
    Keywords: Piroxicam ; β-Cyclodextrin ; pharmacokinetics ; healthy volunteers ; multiple dose ; adverse event
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CHF1194 is an inclusion complex of β-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, β-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-β-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of β-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5′-hydroxypiroxicam and β-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80–125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5′-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with β-cyclodextrin. This may be of therapeutic interest as it might accelerate the onset of pain relief. The pharmacokinetics of piroxicam was linear after the doses used here, suggesting that long term treatment with CHF1194 should not require any change in dosing regimen. Even after 14 days of repeated administration of CHF1194, β-cyclodextrin could not be detected in plasma or urine, suggesting that in man the unchanged oligosaccharide was absorbed to a very small extent.
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  • 12
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    European journal of clinical pharmacology 48 (1995), S. 385-390 
    ISSN: 1432-1041
    Keywords: Furosemide ; Dialysis ; continuous ambulatory peritoneal ; drug disposition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Single doses of oral and intravenous furosemide were given to 8 healthy male volunteers (40 mg) and 11 patients with renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was variable. Only one half of the intravenous dose and one third of the oral dose was available for renal pharmacological action as judged by the urinary recovery. In the patients, absorption was also variable and was markedly delayed (t max 128 vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences between the two groups were not significant, however (95% C.I.: -90 to 30 and -40.4 to 7.5 respectively). The mean elimination half-life was significantly longer in the patients following both the oral (228 vs 65.1 min) and intravenous dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers was 138 ml·min−1 and this was much lower in the CAPD patients (61.9 ml·min−1) in whom the renal clearance was minimal. The peritoneal clearance of furosemide was negligible. Although there were trends indicating differences in absorption between the two groups, the significant differences in furosemide disposition observed in CAPD patients were due to renal failure.
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  • 13
    ISSN: 1432-1041
    Keywords: Caffeine ; Cardio-green ; Indocyanine Green ; altitude ; metabolism ; pharmacokinetics ; hypoxia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardiogreen (ICG) were examined in eight healthy males (23–35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg · kg−1) was administered as an intravenous bolus and caffeine (4 mg · kg−1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in the caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g · 1−1 · min−1), and increased clearance (117 vs 86 ml · min−1 · 70 kg−1). In ALT the area under the curve of ICG significantly decreased (85 vs 207 mg · 1−1 · min−1) and the volume of distribution and clearance increased (5.2 vs 2.41 and 532 vs 234 ml · min−1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.
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  • 14
    ISSN: 1432-1041
    Keywords: Diltiazem ; sustained-release formulation ; pharmacokinetics ; bioavailability ; bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3–4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of 13C-labelled drug: absolute bioavailability of the “once a day” formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.
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  • 15
    ISSN: 1432-1041
    Keywords: Diabetes ; Human insulin ; Lorazepam ; pharmacokinetics ; glucuronidation ; enterohepatic circulation ; animal insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of hepatic glucuronidation. The volume of distribution and clearance of free lorazepam in diabetic patients were not significantly different from the corresponding estimates in 14 normal controls. Neomycin and cholestyramine increased the clearance of lorazepam by 63% consistent with their effect in non-diabetic controls. However, patients on beef/pork insulin exhibited a greater than normal increase on this interupting regimen (125%), and had a significantly greater neomycin/cholestyramine cycling-interrupted clearance of lorazepam than either normal controls or patients on human insulin (15.4 vs. 6.96 and 7.87 ml·min−1·kg−1). The clearance was correlated positively and significantly with HbA1c and glycated proteins (fructosamine), but only in patients on human insulin. Thus, the pharmacokinetics of lorazepam was not altered in patients with insulin-dependent diabetes mellitus. However, it is possible that there are differences in the rate and extent of hepatic glucuronidation and enterohepatic circulation of lorazepam between patients treated with beef/pork and human insulins and between diabetics treated with beef/pork insulin and non-diabetic controls.
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  • 16
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    European journal of clinical pharmacology 48 (1995), S. 273-277 
    ISSN: 1432-1041
    Keywords: Mesalamine ; 5-aminosalicylic acid ; controlled release capsules ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 μg · ml−1 and 1.33 μg · ml−1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.
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  • 17
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    European journal of clinical pharmacology 49 (1995), S. 127-137 
    ISSN: 1432-1041
    Keywords: Thiopental ; Pharmacokinetic modelling ; pharmacokinetics ; single dose ; multiple dosing ; neurosurgical patients ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg−1, and the steady-state volume of distribution (Vss) was 2.16 1·kg−1. The distribution (t1/2α) and elimination (t1/2β) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min−1·kg−1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg·1−1 (mean 16.0 mg·1−1 and median 14.3 mg·1−1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg·1−1 (25.4 mg·1−1, and median 23.3 mg·1−1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg−1. The mean Vss was 2.68 1·kg−1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2α was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2β and the mean residence time became longer due to a decrease in clearance. For t1/2β the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml·min−1·kg−1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.
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  • 18
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    European journal of clinical pharmacology 49 (1995), S. 139-143 
    ISSN: 1432-1041
    Keywords: Intestinal absorption ; Amoxicillin ; pharmacokinetics ; maximum entropy ; input rate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A computer program applying the principle of maximum entropy to the analysis of drug absorption rate has been developed. Plasma concentrations of amoxicillin obtained after oral and intravenous dosing have been analysed, together with simulated data corresponding to a complex input. Amoxicillin absorption rates devised by the program were similar to those obtained by a standard deconvolution method, although they were displayed as an almost continuous profile. However, improbable fluctuations were obtained with some data sets and the fraction absorbed was underestimated by 13%. With the simulated data, the maximum entropy program did not provide a better solution than the standard deconvolution procedure, and it was sensitive to the addition of random error and to the number of samples. The maximum entropy principle, as implemented in our computer program, may not have a better performance than standard deconvolution procedures, especially in human experiments where the number of blood samples is usually limited.
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  • 19
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    European journal of clinical pharmacology 52 (1997), S. 235-237 
    ISSN: 1432-1041
    Keywords: Key words Itraconazole ; Coca Cola; acidic beverage ; absorption ; pharmacokinetics ; drug concentration ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml−1, the mean Cmax was 0.14 vs 0.31 μg · ml −1and the mean tmax was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola.
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  • 20
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    European journal of clinical pharmacology 52 (1997), S. 289-292 
    ISSN: 1432-1041
    Keywords: Key words Nicardipine; enantiomers ; healthy volunteers ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P 〈 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose.
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  • 21
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    European journal of clinical pharmacology 52 (1997), S. 379-381 
    ISSN: 1432-1041
    Keywords: Key words Nitroglycerin; transdermal nitrate ; pharmacokinetics ; patch renewal ; exercise test
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. Methods: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. Results and conclusions: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.
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  • 22
    ISSN: 1432-1041
    Keywords: Key words Angiotensin II ; Valsartan; AT1 receptor antagonist ; healthy volunteers ; pharmacokinetics ; renin-angiotensin system ; blood pressure ; passive tilting
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet. Methods: This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. Results: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t½λ1 〈 1 h), followed by a slower terminal elimination phase (t½λ2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of −3.6 and −2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (−2.0 mmHg) and day 8 (−4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats · min−1 on day 1 and by 2.9 beats · min−1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion. Conclusions: Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.
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  • 23
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    European journal of clinical pharmacology 51 (1997), S. 359-366 
    ISSN: 1432-1041
    Keywords: Key words Sufentanil ; pharmacokinetics ; haemo dynamics ; different infusion rates ; coronary surgery
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract    Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg−1 sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg−1 · min−1, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min−1 · kg−1), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg−1) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean Cmax values of 421 (group I), 125 (group II), and 53 (group III) ng · ml−1 and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg−1 tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate.
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  • 24
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    European journal of clinical pharmacology 51 (1997), S. 415-419 
    ISSN: 1432-1041
    Keywords: Key words Midazolam ; Fluconazole ; CYP3A4 ; interaction ; pharmacokinetics ; pharmacodynamics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0–3, AUC0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0–3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
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  • 25
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    European journal of clinical pharmacology 51 (1997), S. 421-425 
    ISSN: 1432-1041
    Keywords: Key words Warfarin ; Meloxicam ; interaction ; pharmacokinetics ; protein binding
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCSS values for the more potent S-enantiomer were 5.07 mg · h · l−1 (27.5%) for warfarin alone and 5.64 mg · h · l−1 (28.1%) during the interaction phase. Respective AUCSS values for R-warfarin were 7.31 mg · h · l−1 (43.8%) and 7.58 mg · h · l−1 (39.1%). Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.
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  • 26
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    European journal of clinical pharmacology 52 (1997), S. 391-396 
    ISSN: 1432-1041
    Keywords: Key words Lansoprazole ; CYP2C19; genotype ; hydroxy lation ; polymorphism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the genetic polymorphism of CYP2C19 which occurred by two mutations, CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects. Methods: Polymerase chain reaction (PCR) restriction fragment length polymorphism procedures were used to detect the CYP2C19m1 mutation in exon 5 and the CYP2C19m2 mutation in exon 4 using SmaI and BamHI, respectively. Results: Ten subjects were homozygous (wt/wt subjects) for the wt allele in both exon 5 and exon 4, four subjects were heterozygous (wt/m1) for the CYP2C19m1 mutation, and two subjects were heterozygous (wt/m2) for the CYP2C19m2. The remaining four subjects had both mutated alleles in CYP2C19 genes, i.e., two were homozygous (m1/m1) for the defect in exon 5 and two were heterozygous (m1/m2) for the two defects in exons 5 and 4. The subjects in group 1 (wt/wt, wt/m1 and wt/m2) were the extensive metabolizers (EMs) for 5-hydroxylation of lansoprazole and were in the range of hydroxylation indexes from 3.83 to 19.8, whereas the subjects in group 2 (m1/m1 and m1/m2) were the poor metabolizers (PMs) and the indexes were in the range of 38.5 to 47.6. In group 2, AUC, t1/2 and CL/f of lansoprazole were significantly greater, longer, and lower, respectively, than those in group 1. Conclusion: The hydroxylation of lansoprazole to 5-hydroxylansoprazole was apparently impaired in the subjects with the genetic defects of CYP2C19 (m1/m1 or m1/m2).
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  • 27
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    European journal of clinical pharmacology 47 (1995), S. 543-548 
    ISSN: 1432-1041
    Keywords: Sumatriptan ; pharmacokinetics ; single dose ; bioavailability ; dose proportionality ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Sumatriptan is classified as a vascular 5HT1 receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration. The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h. Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.
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  • 28
    ISSN: 1432-1041
    Keywords: Granisetron ; pharmacokinetics ; elderly ; tolerance
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  • 29
    ISSN: 1432-1041
    Keywords: Growth hormone ; Jet-injection ; pharmacokinetics ; pharmacodynamics ; Somatomedin C ; free fatty acids
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of recombinant human growth hormone (rhGH) were studied after a single subcutaneous dose given by jet-injection, and have been compared with the results obtained after conventional needle-injection. Twelve healthy male volunteers completed an open label, randomised, two-way crossover study, with a 7-day washout period between the two single sc doses. Pharmacokinetic parameters were derived from rhGH concentrations in blood samples collected regularly over 24 h after dosing on Day 1 of each period. To investigate the pharmacodynamics, additional samples were taken for the analysis of somatomedin C (IGF-I) and free fatty acids (FFA). A higher and earlier Cmax was found after jet-injection (ratio (%) jet-injected/needle-injected 124; 90%-confidence interval 108 – 142). The AUC0−∞ for rhGH were similar (ratio (%) jet-injected/needle-injected 98; 90%-confidence interval 93 – 103). Both treatments were associated with a significant and similar rise in IGF-I. Both administrations of rhGH were associated with identical rhythmical changes in FFA. The study indicates that jet-injected and needle-injected rhGH are bioequivalent with respect to the amount absorbed. The criterion for bioequivalence is not met for the rate of absorption. It is unlikely that the latter finding will influence the pharmacodynamics of rhGH, since bioequipotency was established for the effect on IGF-I generation. Jet-injection was safe in use and was generally well tolerated.
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  • 30
    ISSN: 1432-1041
    Keywords: Losartan ; Cimetidine ; pharmacokinetics ; plasma renin activity
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This was a 2-period randomized, crossover study in 8 healthy males to determine the effects of cimetidine (400 mg q.i.d. for 6 days) on the pharmacokinetics and pharmacodynamic effects of the angiotensin II receptor antagonist, losartan (100 mg). Cimetidine increased the AUC for losartan 18% without affecting the AUC for E-3174, the active metabolite of losartan. The increase in plasma renin activity following losartan was not affected by cimetidine (maximum mean increases 12.6 and 12.1 ng Ang I·ml−1·h−1 without and with cimetidine, respectively). These results indicate that cimetidine does not appear to alter the pharmacokinetics or pharmacodynamics of losartan to a clinically significant extent.
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  • 31
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    European journal of clinical pharmacology 48 (1995), S. 501-504 
    ISSN: 1432-1041
    Keywords: Quinidine ; CYP2D6 ; Sparteine oxidation polymorphism ; (3S)-3OH-quinidine ; quinidine-N-oxide ; dihydroquinidine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l·h−1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l·h−1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.
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  • 32
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    European journal of clinical pharmacology 49 (1995), S. 221-228 
    ISSN: 1432-1041
    Keywords: Nefazodone ; Geriatric assessment ; Hepatic cirrhosis ; Renal impairment ; pharmacokinetics ; antidepressive agents
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects ≤55 years of age (YNG), 12 elderly subjects ≥65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20–60 ml·min−1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not. Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.
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    European journal of clinical pharmacology 49 (1995), S. 229-235 
    ISSN: 1432-1041
    Keywords: Nefazodone ; Renal impairment ; pharmacokinetics ; antidepressive agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CLCR≥72 ml·min−1·1.73 m−2, 6 with moderate (MOD) renal impairment, CLCR 31–60 ml·min−1·1.73 m−2 and 9 with severe (SEV) renal impairment, CLCR≤30 ml·min−1·1.73 m−2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (Cmin) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state Cmax within 2 h after administration of nefazodone; tmax for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and Cmax, and elimination t1/2 values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.
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  • 34
    ISSN: 1432-1041
    Keywords: Felodipine ; pharmacokinetics ; haemodynamics ; congestive heart failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In congestive heart failure patients the kinetics of felodipine, a dihydropyridine calcium antagonist, show interpatient differences after acute i.v. administration that disappear after 8 weeks oral treatment with a change in kinetics in the patients with the largest clearances (CL) and the smallest volumes of distribution (V SS). Pharmacokinetic and haemodynamic data were combined to construct a haemodynamic-pharmacokinetic model. This model shows that the differences between the patients in i.v. pharmacokinetics are consistent with a difference in plasma flow distribution between liver and poorly perfused tissues. In patients in whom kinetics changed, felodipine treatment is supposed to cause a redistribution of flow from liver to peripheral tissues, accompanied by a decreased work load of the heart and a larger increase in VO2max during therapy than in the other patients, whose workload increased. This suggests a better therapeutic response in the patients whose kinetics changed. As change in kinetics is related to felodipine CL and CL to liver plasma flow, felodipine CL or even indocyanine CL might be predictive for the therapeutic effect of felodipine.
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  • 35
    ISSN: 1432-1041
    Keywords: Cholesterol acyltransferase ; Hypocholesterolaemic ; 447C88 ; volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 447C88 (N-Heptyl-N′-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng·ml−1 (23 nM). It is poorly absorbed but 5 mg·kg−1·day−1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food. All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng·ml−1 and 9.0 ng·ml−1·h after 200 mg rising to 5.4 ng·ml−1 and 23.8 ng·ml−1·h respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.
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  • 36
    ISSN: 1432-1041
    Keywords: Key words Felodipine ; Dietary interaction ; Flavonoids; pharmacodynamics ; pharmacokinetics ; grapefruit juice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and Cmax by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in Cmax. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism.
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  • 37
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    European journal of clinical pharmacology 52 (1997), S. 307-310 
    ISSN: 1432-1041
    Keywords: Key words Artemether ; Thai males; malaria ; dihydroartemisinin ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t 1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t 1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).
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  • 38
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    European journal of clinical pharmacology 52 (1997), S. 403-406 
    ISSN: 1432-1041
    Keywords: Key words Oxybutynin ; Itraconazole; N-desethyloxy‐butynin; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0–t) and the peak concentration of oxybutynin twofold. The AUC0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.
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  • 39
    ISSN: 1432-1041
    Keywords: Key wordsDraflazine ; Population analysis; nucleoside transport inhibitor ; non-linear red blood cell partition ing ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22–55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg · h−1) and variable duration (2–24 h). Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. Results: The population typical value for the dissociation constant K d (%CV) was 0.648 (12) ng · ml−1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng · ml−1 RBC. The interindividual variability (%CV) was moderate for K d (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2βaveraged 11.0–30.5 h and the mean CL from the plasma was 327 to 465 ml · min−1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2β was 30.2 to 42.2 h and the blood CL averaged 17.4–35.6 ml · min−1. Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg · h−1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.
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  • 40
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    European journal of clinical pharmacology 16 (1979), S. 203-209 
    ISSN: 1432-1041
    Keywords: dantrolene sodium ; spasticity ; twitch tension ; dose response ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dantrolen sodium is a muscle relaxant, which is used in the treatment of spasticity. Although it is given chronically, little is known about its pharmacokinetic behaviour. The relationship between the effect of a single oral dose of dantrolene sodium and its plasma concentration in healthy volunteers was studied by measuring the effect on the twitch tension, and in spastic patients on the decrease in muscle hypertonia. On the twitch tension dantrolene gave a depression of 49.1±9.4% (±SD) within 1.15 and 3.45 h after ingestion of 100 mg. The mean maximal plasma concentration was 1.24±0.32 µg/ml (±SD). The effect and the plasma concentration were correlated. No relationship between the plasma concentration of dantrolene sodium and its effect could be established in patients, although definite activity in 6 out of 7 patients was observed after a single oral dose of 100 mg, and plasma concentration of dantrolene sodium greater than 0.3 µg/ml were consistently associated with better results than placebo treatment in 6 out of 7 patients.
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  • 41
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    European journal of clinical pharmacology 16 (1979), S. 287-293 
    ISSN: 1432-1041
    Keywords: linear system theory ; perfusion model ; cardiac output ; pulmonary extraction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Assessment of pharmacokinetics in terms of circulatory drug transport is proposed using the methods of linear system theory. In this model-independent approach drug distribution and disposition are characterized by the total extraction ratio, the mean residence time in the body and the volume of distribution at steady state. In analyzing concentration(c)-time(t) data, the procedure requires calculation only of the areas under the c(t)-and c(t)×t-curves to estimate kinetic parameters, and for prediction of the steady state concentration following continuous infusion or multiple doses. Pulmonary clearance of drugs is included in the theory.
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  • 42
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    European journal of clinical pharmacology 12 (1977), S. 137-145 
    ISSN: 1432-1041
    Keywords: Chlormethiazole ; pharmacokinetics ; metabolites ; oral administration ; young and elderly human subjects ; quantitative gas chromatographymass spectrometry ; whole blood distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of chlormethiazole and two of its metabolites has been measured in three young and three aged human subjects following administration of a single oral dose of chlormethiazole. A sensitive analytical method based on gas chromatography-mass spectrometry using the selective ion monitoring mode of operation was developed to permit quantitation of the plasma levels. The time course of the plasma concentration of chlormethiazole and metabolites showed wide inter-subject variation, particularly between the young and elderly subjects. Absorption of chlormethiazole was rapid in the subjects of both groups as assessed by the time taken to reach the peak plasma concentration. The mean peak plasma level of chlormethiazole was more than five times greater in the elderly (2.90±1.56 µg/ml) than in the young (0.55±0.58 µg/ml) subjects. The plasma level of chlormethiazole was consistently higher in the aged subjects and this was reflected by the larger area under the plasma curve in aged (7.62±5.37 µg.h/ml) than in young (0.94±0.66 µg.h/ml) individuals. Decreased pre-systemic elimination by the liver has been suggested as an important factor contributing to the higher plasma level in the elderly. Estimates of absolute systemic availability, calculated by reference to previous intravenous studies, were greater for the elderly subjects. The distribution of chlormethiazole in whole blood from six young and six elderly human subjects was investigated in vitro. The unbound fraction of chlormethiazole in plasma increased significantly from 0.308±0.035 in young subjects to 0.403±0.067 in the elderly. Distribution of the drug in whole blood was different for the two age groups; the fraction of drug distributed to plasma water was significantly greater and the fraction in blood cells was significantly less in the aged.
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  • 43
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    European journal of clinical pharmacology 12 (1977), S. 171-174 
    ISSN: 1432-1041
    Keywords: Tolamolol ; hypertension ; pharmacokinetics ; mean steady-state concentration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolamolol was administered in a “double-blind” study to fifteen hypertensive patients by dose-titration against arterial blood pressure. Mean steady-state plasma tolamolol concentrations (Css) were determined for each patient from the area under the plasma concentration — time curve during a dosage interval whilst patients were receiving optimal tolamolol doses. No significant correlation was observed between daily tolamolol dose and Css; the relationship between fall in lying mean arterial pressure and Css also failed to reach conventional levels of statistical significance, but Css was observed to be correlated with the fall in standing pressure. The results suggest that plasma concentrations in excess of 200 ng/ml may be required to achieve an effective hypotensive response with the drug.
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  • 44
    ISSN: 1432-1041
    Keywords: Muzolimine ; pharmacodynamics ; pharmacokinetics ; furosemide ; saluresis
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a biometrically planned, double-blind study on 12 Oedema-free male patients the saluretic effect of muzolimine 30 mg was compared with furosemide 40 mg. The plasma level of muzolimine was determined and correlated with its pharmacodynamics. In terms of excretion during the 12-hour observation period muzolimine 30 mg had as great a cumulative effect as furosemide 40 mg. There was a significant difference in the time-response curve. During the first two hours furosemide 40 mg had more saluretic effect than muzolimine 30 mg. Between two and four hours there was no significant difference between the two substances. Between four and six hours, however, muzolimine was somewhat more effective than furosemide, although the difference did not reach the level of significance. After 6 h there was no longer any difference between the two compounds. The half-life of the fall in concentration of muzolimine in plasma was 3.7 up to 10 h after its administration. The time-response curve of the increased urine excretion correlated well with the time course of the concentration of muzolimine in plasma.
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  • 45
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    European journal of clinical pharmacology 12 (1977), S. 125-132 
    ISSN: 1432-1041
    Keywords: Valproic acid ; pharmacokinetics ; saliva concentration ; urinary excretion ; serum protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9±2.6 h in the single dose and 17.3±3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064±0.0011 l/kg×h. The apparent volume of distribution was small at 0.15±0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3±13.0 µg/ml. Css observed was lower than Css predicted (99.2±14.7 µg/ml) from single dose kinetics (p〈0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7±0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.
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  • 46
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    European journal of clinical pharmacology 12 (1977), S. 367-373 
    ISSN: 1432-1041
    Keywords: Sulphamethizole ; tetracycline ; doxycycline ; rest ; exercise ; pharmacokinetics ; excretion ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7–8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p〈0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.
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  • 47
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    European journal of clinical pharmacology 13 (1978), S. 275-284 
    ISSN: 1432-1041
    Keywords: Diazepam ; pharmacokinetics ; pregnant women ; plasma clearance ; blood/plasma concentration ratio ; placental transfer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of diazepam has been studied in pregnant women at parturition. The plasma concentration of diazepam was monitored for at least 3 days in 18 women who received a single intravenous injection of 10 mg during the 10 h-period prior to delivery. Fourteen mothers had uneventful puerperia (Group I) and in 13 of these cases there was a pronounced postnatal increase in the plasma concentration of diazepam. The terminal phase half-life (t1/2) was significantly greater for Group I (mean = 65 h; range = 24–114 h) than for age-matched non-pregnant patients (mean = 29 h; range = 18–44 h from literature). The prolonged t1/2 appeared to be related to changes in the distribution of diazepam and not to a reduction in hepatic elimination since the total plasma clearance (Cltp) in these 14 pregnant patients (mean = 28 ml/min; range = 18–43 ml/min) was not reduced compared to that reported for non-pregnant controls (mean = 30 ml/min; range = 22–45 ml/min). Four mothers underwent postnatal surgery for tubal ligation (Group II) and the plasma concentration-time profiles for this group did not show the same postnatal phenomenon as did the profiles obtained for Group I. The t1/2 for Group II was shorter (mean = 31 h; range = 24–37 h) than for Group I and similar to that for the non-pregnant controls. The Cltp for Group II was greater (mean = 56 ml/min; range = 48–63 ml/min) than for both Group I and non-pregnant controls. These results suggest that delivery alters the disposition of diazepam and is generally associated with a postnatal re-distribution of diazepam into the systemic circulation. The blood/plasma concentration ratio was determined in 9 patients (mean = 0.62; range = 0.54–0.77). There was no difference in the total blood clearance between the pregnant patients of Group I and the non-pregnant controls. In most cases the umbilical venous plasma concentration (Cpuv) of diazepam was greater than the peripheral maternal venous plasma concentration (Cpmv) at delivery. The foetus appears to constitute a slowly equilibrating tissue-group in which diazepam does not reach equilibrium with the maternal systemic circulation for at least 5–10 h at which time the diazepam concentration in maternal and foetal plasma is similar.
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  • 48
    ISSN: 1432-1041
    Keywords: p-Chlorophenoxyisobutyric acid ; clofibrate ; steady-state plasma concentrations ; bioavailability ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations and bioavailability of clofibrinic acid have been estimated under conditions approaching the steady-state during a ten-day period of administration as clofibrate or as a calcium clofibrinate-carbonate combination (1:1 w/w) at a dosage interval of 12 h. Formulation — related differences in bioavailability were not significant, and the 95% confidence limits of these differences were within −2% to +8% of the mean for the reference formulation of clofibrate. The mean steadystate plasma concentrations of clofibrinic acid measured on the tenth day of dosing were 116 µg/ml±22 S.D. and 119 µg/ml±23 S.D. after administration of 885 mg as clofibrate and the calcium clofibrinate-carbonate combination respectively. The peaks of mean plasma concentrations were 70 µg/ml±15 S.D., 119 µg/ml±32 S.D. and 131 µg/ml±26 S.D. on the first, fifth and tenth day of dosing with clofibrate, and 62 µg/ml±13 S.D., 127 µg/ml±S.D. and 143 µg/ml±25 S.D. on the corresponding days of dosing with the calcium clofibrinate-carbonate combination. After the last dose on the tenth day of dosing, the mean apparent half-lives of elimination of clofibrinic acid from plasma were 24.2 h±4.4 S.D. and 25.5 h±3.2 S.D. after administration of clofibrate and the calcium clofibrinate-carbonate combination respectively.
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  • 49
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    European journal of clinical pharmacology 13 (1978), S. 69-72 
    ISSN: 1432-1041
    Keywords: Phenazone ; pharmacokinetics ; hydrocortisone ; elimination rate ; distribution volume
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a high plasma concentration of hydrocortisone on the metabolism of phenazone in humans has been studied. Two series of experiments were carried out, Group A to demonstrate any enzyme-inducing effect of hydrocortisone, and Group B to study the immediate effect of hydrocortisone on the metabolism of phenazone. 9 subjects (Group A) received a total 250–400 mg hydrocortisone i.m. twice daily for three days and the 24-hour elimination of phenazone was studied before and afterwards. In a further 5 subjects (Group B) the elimination of phenazone was examined during administration of hydrocortisone or placebo. The elimination rate and the apparent volume of distribution of phenazone remained unchanged under both experimental conditions.
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  • 50
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    European journal of clinical pharmacology 13 (1978), S. 97-101 
    ISSN: 1432-1041
    Keywords: Clonidine ; plasma level ; pharmacokinetics ; steady state ; urinary excretion ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single oral dose of clonidine 300 µg was administered to 8 healthy, normotensive subjects and the time course of its plasma concentrations was followed for 24 h. The plasma concentration of clonidine rose to a peak of 1.17±0.12 ng/ml at about 2 h: the absorption half-life was 0.6±0.2 h. Elimination followed first order kinetics with a half-life of 7.7±2.0 h. The correlation between the two most common side-effects of clonidine, sedation and dryness of the mouth, with the time course of its plasma concentrations was highly significant, p〈0.01. All the subjects complained of severe sedation. During continuous administration of clonidine (75 µg t.i.d.) for one week a steady state serum level of 0.30–0.35 ng/ml was achieved. One 75 µg tablet of clonidine raised the serum level to about 0.69±0.13 ng/ml in two hours. After cessation of dosing, the serum level declined with a half-life of 7.5±1.5 h. The urinary excretion of unchanged clonidine was found to be about onethird of the administered dose in 24 h during continuous administration and in the first 24 h after the single oral dose.
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  • 51
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    European journal of clinical pharmacology 14 (1978), S. 203-212 
    ISSN: 1432-1041
    Keywords: Mepivacaine ; pharmacokinetics ; neonates ; healthy adults ; metabolism ; renal excretion ; lignocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of mepivacaine has been studied in premature neonates dosed subcutaneously and in healthy adults dosed intravenously. The pharmacokinetics of mepivacaine in four neonates (N) was compared with that in six adults (A). Newborns had a significantly longer terminal phase half-life than adults (N mean 8.69 h; A mean 3.17 h). Total plasma clearance normalized on body weight was significantly smaller in neonates (mean 2.34 ml/min/kg) than in adults (mean 5.47 ml/min/kg), as was the hepatic blood clearance (N mean 1.37 ml/min/kg; A mean 5.10 ml/min/kg). The renal plasma clearance, however, was significantly greater in neonates (mean 0.76 ml/min/kg) than adults (mean 0.20 ml/min/kg). There was an average six-fold increase in the fraction of the dose excreted unchanged in newborns (mean 43.3%) compared to adults (mean 7.1%) with acidified urine (pH 5.5–6.0). There was significantly more of the mono-N-demethylated metabolite of mepivacaine excreted by newborns (mean 11.4%) than by adults (mean 2.2%), but their capacity to carry out aromatic hydroxylation of mepivacaine was negligible. These results for mepivacaine were compared with those previously reported for lignocaine in premature infants. The immaturity of hepatic function appears to have diminished more profoundly the ability of premature infants to metabolize mepivacaine than lignocaine. These findings are discussed in terms of perfusion theory of hepatic drug elimination.
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  • 52
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    European journal of clinical pharmacology 14 (1978), S. 143-147 
    ISSN: 1432-1041
    Keywords: Children ; leukemia ; high-dose methotrexate ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous high-dose methotrexate were studied in two groups of children being treated for malignant diseases, mostly acute lymphatic leukemia. The peak serum level of methotrexate of 2.32·10−5 mol/l was found in children given 500 mg methotrexate/m2 by a 24 h infusion, and another group given 2790 mg/m2 during a 6 h infusion had serum levels as high as 2.16·10−4 mol/l. The decay of serum concentration of methotrexate after completion of the infusion followed a diphasic curve, with an initial serum half-life of 4.8 h, followed by a second half-life of 34.4 h at distribution equilibrium. The apparent volume of distribution was 56.8 litres/m2. Significant levels of methotrexate were found in cerebrospinal fluid, but penetration into cerebrospinal fluid was slow. Urinary excretion of methotrexate was considerable. Four to five days after commencement of the infusion, urinary concentrations of methotrexate still exceeded the serum levels.
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  • 53
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    European journal of clinical pharmacology 19 (1981), S. 263-269 
    ISSN: 1432-1041
    Keywords: chlormethiazole ; pharmacokinetics ; pharmacodynamics ; sedatives ; blood concentrations ; amnesia
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chlormethiazole ethanedisulphonate (0.8%) (Hemineurin, Astra) was administered to 10 healthy unpremedicated volunteers at a constant-rate infusion of 2.5 ml/min for 60 min (Phase 1, n=5) and 113 min (Phase 2, n=5). With one exception, chlormethiazole blood concentration-time data were described by a two-compartment open model. Total body clearance was the same in both phases (1.15 l · min−1, SD 0.49; and 1.05 l · min−1, SD 0.36 respectively) and was similar to the clearance of indocyanine green. No correlation was found between clearance, initial dilution volume (137 l, SD 62; and 125 l, SD 33 in 1 and 2 phases respectively) or volume of distribution at steady-state equilibrium (308 l, SD 91; and 224 l, SD 59) with either body weight or estimated lean tissue mass. Slow half-life was 289 min (SD 169) in Phase 1 and 253 min (SD 172) in Phase 2. Moderately heavy sedation associated with amnesia while retaining the ability to readily obey verbal commands was achieved in one subject of Phase 1 and 4 subjects of Phase 2 and occurred at a mean chlormethiazole ethanedisulphonate blood concentration of 9.2 mg · l−1 (SD 2.9). Transient nasal irritation was experienced by all subjects during the initial stages of infusion. A rise in pulse rate (33%, SD 8) was a prominent feature but blood pressure and respiratory rates were very stable.
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  • 54
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    European journal of clinical pharmacology 14 (1978), S. 335-340 
    ISSN: 1432-1041
    Keywords: Drug binding to muscle ; interindividual differences ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Binding of 22 drugs to human muscle tissue has been determined by ultrafiltration. All drugs tested were bound, the bound fraction ranging from 13% (aminophenazone) to 〉98% (desipramine). Both linear and nonlinear binding was observed. For chemically related substances, binding to muscle tissue correlated with plasma binding and lipid solubility. There were significant differences in binding to muscle from different individuals. With respect to pharmacokinetics of drugs, it is suggested that binding to muscle tissue may be at least as important as plasma binding.
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  • 55
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    European journal of clinical pharmacology 15 (1979), S. 275-280 
    ISSN: 1432-1041
    Keywords: Parkinson's disease ; bromocriptine ; pharmacokinetics ; plasma concentration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (Cmin) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the Cmin. First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.
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  • 56
    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; food effect on bioavailability ; repeated administration ; pharmacodynamics ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.
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  • 57
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    European journal of clinical pharmacology 15 (1979), S. 341-347 
    ISSN: 1432-1041
    Keywords: clofibrate ; chlorophenoxyisobutyric acid ; disposition ; hepatitis ; cirrhosis ; renal failure ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min−1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg−1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min−1) and plasma clearance of the unbound drug (81 vs. 243 ml×min−1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.
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  • 58
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    European journal of clinical pharmacology 15 (1979), S. 363-366 
    ISSN: 1432-1041
    Keywords: methotrexate ; protein binding ; ultrafiltration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of methotrexate by serum from eight normal volunteers was assessed by continuous ultrafiltration at pH 7.4 and 37°C. Methotrexate concentrations were measured by radioimmunoassay and the data analysed by the method of Scatchard. The major binding protein was albumin which bound 87.3% of the drug in serum. Analysis of the Scatchard plots indicated two distinct groups of binding sites. Class I was found to have 0.16±0.05 (S D) binding sites with an intrinsic association constant of 71.15±35.98 (S D)×104 M−1: Class II had 2.01±0.93 (S D) binding sites and an affinity of 0.18±0.15×104 M−1. No great change in the percentage of methotrexate bound occurred until the total concentration of the drug exceeded 50 µMol 1−1.
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  • 59
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    European journal of clinical pharmacology 20 (1981), S. 147-155 
    ISSN: 1432-1041
    Keywords: azapropazone ; cirrhosis ; renal failure ; non-steroidal anti-inflammatory drug ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of azapropazone 600 mg i.v. was investigated in 6 healthy subjects, 13 patients with cirrhosis and 8 patients with renal failure. In healthy subjects the elimination half-life was 12.2±2.1 h (mean ± SD), the volume of distribution 10.6±3.31 and the total clearance was 597±135 ml·h−1. Renal clearance accounted for about 62% of the total clearance. The free fraction of azapropazone in the plasma was 0.0045±0.0006. The patients with cirrhosis were divided into Group I with modest and Group II with severe impairment of liver function. In Group I the total clearance of azapropazone was not significantly different from that in healthy subjects. There was a 2.5-fold increase in its free fraction in plasma, and a reduction in the free drug clearance to about half that in healthy subjects. In Group II patients total clearance was reduced to about 20% of normal. This was partly due to reduced non-renal clearance but mainly to impaired renal clearance of azapropazone. The diminished renal clearance was considered at least in part to represent a drug-induced impairment of renal function, as there was a concomitant reduction in creatinine clearance. The free fraction of azapropazone in the plasma was markedly enhanced (〉0.02), and simultaneously, free drug clearance was drastically reduced, to about 2% of that in healthy subjects. In patients with renal failure the total clearance was diminished, depending on the degree of impairment of kidney function. Anephric patients were estimated to have about one third of the total clearance in normal subjects. The free fraction of azapropazone in the plasma was increased in 4 of the 8 patients. It is concluded that patients with cirrhosis and modest impairment of liver function may require about half the normal dose of azapropazone, since free drug clearance is reduced by about 50%. Patients with severe impairment of liver function are expected to be highly susceptible to dose-related side effects, since the pronounced increase in the free fraction in plasma and the decreases in renal and non-renal clearance lead to marked reduction in free drug clearance and so to accumulation of free drug in the body. In patients with renal failure the dose of azapropazone should be reduced according to the degree of impairment of kidney function and plasma protein binding of the drug.
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  • 60
    ISSN: 1432-1041
    Keywords: pindolol ; beta-blockade ; slow release tablet ; plasma levels ; urinary excretion ; pharmacokinetics ; pharmacodynamics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy volunteers the time course of cardiac beta-adrenoceptor blocking activity, plasma levels and cumulative urinary excretion of pindolol were compared during a 4-day course of pindolol 5 mg (Visken®) t. d. s., and one tablet of pindolol 20 mg retard (Visken® retard) once a day. After oral administration of the 20 mg retard tablet, plasma concentrations of pindolol higher than half the maximum value (1/2 Cp (tmax)) were maintained about 2.5 times as long as after administration of the conventional 5 mg tablet. This is evidence for an important and marked retardation of drug release. During treatment with pindolol 20 mg retard once daily, cardiac beta-adrenoceptor blockade, measured by the reduction in exercise-induced tachycardia and in the exercise-induced rise in systolic blood pressure, at almost all times throughout the 24 h period was at least as great as during treatment with pindolol 5 mg t. d. s. This suggests that patients successfully treated with pindolol 5 mg t. d. s. can be maintained with the same beta-adrenoceptor blockade by a single tablet of pindolol 20 mg retard once daily.
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  • 61
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release tablet ; absolute bioavailability ; pharmacokinetics ; individual dosage regimen
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic disposition of theophylline after taking a new, sustained release tablet (Theolair Retard® 250 mg, Theolair S. R.®, Riker Laboratories) has been studied in 8 hospitalized patients. Absolute bioavailability was determined from the ratios of the areas under the serum concentration-time curves after intake of the tablet and after intravenous infusion of aminophylline in the same patient. The absolute bioavailability of Theolair Retard® 250 mg was 110.9±20.8% (mean ± SD). Maximal serum concentrations were reached after 7.3±3.5 h, the large intersubject variation being due to differences in gastric emptying time. The tablets appear to release theophylline slowly in acid conditions, but more rapidly in an alkaline medium. Invasion was found to be either monophasic with a rate constant of about 0.8 h−1 (intestine), or biphasic with rate constants of 0.2 h−1 (stomach) and 0.8 h−1 (intestine). The peak levels accounted for 7.9±2.2 mg · 1−1. The profiles of the serum concentration-time curves were such that the concentrations remained above 80% of cmax for 6.5±3.3 h. The relevant pharmacokinetic parameters (half-life of elimination, total body clearance and volume of distribution) were determined and were used to calculate the individual dosage regimens required to obtain therapeutic serum concentrations. The optimal dosing interval to obtain an average steady state serum concentration of 12.5 mg · l−1 was 9.8±3.1 h.
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  • 62
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    European journal of clinical pharmacology 21 (1981), S. 61-64 
    ISSN: 1432-1041
    Keywords: acenocoumarol ; anticoagulant therapy ; breast feeding ; breast milk ; neonatal thrombotest ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 20 women receiving Sintrom® post partum, the acenocoumarol concentration in serum and breast milk at different times was measured. Even at the time of maximal serum concentration, or for the following 6 h, no acenocoumarol could be detected in the breast milk. In accordance with this finding, no effect of breast feeding on Thrombotest values of the infants could be demonstrated. These data suggest that mothers taking acenocoumarol for a short period may safely breast feed their infants.
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  • 63
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    European journal of clinical pharmacology 21 (1981), S. 45-52 
    ISSN: 1432-1041
    Keywords: caffeine ; pharmacokinetics ; plasma ; saliva ; urinary elimination
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and salivary caffeine concentrations were measured by gas-liquid chromatography in 6 healthy caffeine-free volunteers following oral administration of 50, 300, 500 and 750 mg caffeine. Caffeine was also given to a single subject intravenously in doses of 300, 500 and 750 mg. Caffeine was rapidly absorbed and was completely available at all doses. The apparent first-order elimination rate constant decreased linearly with dose and was 0.163±0.081 h−1 for 50 mg and 0.098±0.027 h−1 for 750 mg. The total body clearance was unaffected by dose and was 0.98±0.38 ml/min/kg. There was a trend towards increasing apparent volume of distribution with increasing dose. A linear relationship existed between the area under the plasma concentration, time curve and dose and dose-normalised plasma concentration, time plots were superimposable. These findings suggest that caffeine obeys linear pharmacokinetics over the dose range investigated. Despite significant inter-individual differences in pharmacokinetic parameters there was good reproducibility within 5 subjects given 300 mg caffeine orally on 3 occasions. Salivary caffeine levels probably reflect the unbound plasma caffeine concentration and can be used to estimate the pharmacokinetic parameters of the drug. Overall the saliva/plasma concentration ratio was 0.74±0.08 but within subjects some time-dependence of the ratio was found with higher ratios initially (even after intravenous administration) and lower ratios at longer time intervals after the dose. Urinary elimination of caffeine was low and independent of dose: 1.83% of the dose was eliminated unchanged.
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  • 64
    ISSN: 1432-1041
    Keywords: cyclobarbital ; aminopyrine ; liver disease ; 14CO2 breath test ; barbiturate ; pharmacokinetics ; hepatic drug metabolism ; cirrhosis ; alcoholic liver disease ; viral hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The exhalation of 14CO2 derived from an i.v. tracer dose of [dimethylamine-14C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled 14CO2 occurred 0.5–2 h after 14C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of 14CO2 exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.
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  • 65
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    European journal of clinical pharmacology 26 (1984), S. 121-124 
    ISSN: 1432-1041
    Keywords: methotrexate ; psoriasis ; pharmacokinetics ; plasma levels ; urinary excretion ; renal clearance ; tubular absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500–800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52–102 ml/min (mean±SD, 83±19.4 ml/min).
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  • 66
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    European journal of clinical pharmacology 26 (1984), S. 87-93 
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; renal elimination ; renal insufficiency ; healthy subjects ; creatinine clearance ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, Vβ and Vss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.
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  • 67
    ISSN: 1432-1041
    Keywords: sulphapyridine ; sulphasalazine ; pharmacokinetics ; rectal administration ; oral administration ; plasma levels ; ulcerative colitis
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Rectal administration of sulphasalazine to patients with ulcerative colitis has recently been shown to have similar therapeutic activity but fewer side effects than oral treatment. The present study is a comparison of the pharmacokinetics of sulphasalazine (SASP) and its metabolite sulphapyridine (SP) after rectal and oral administration of SASP to 6 patients with ulcerative colitis. The areas under the concentration-time curves (AUC) and the maximum concentrations (Cmax) of SASP and SP were significantly lower after rectal than oral administration of SASP (p〈0.05). These findings support the view that the lower frequency of side effects after rectal administration of SASP may result from the lower plasma levels of SASP and SP.
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  • 68
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    European journal of clinical pharmacology 26 (1984), S. 309-313 
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; therapeutic window ; steady state concentration ; pharmacokinetics ; cardiovascular effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was given orally as monotherapy in increasing daily doses from 3.1 to 25.7 µg/kg to patients with essential hypertension (n=6). When a steady state concentration in plasma was reached at each dose level, the blood pressure (BP) and heart rate were measured during a dosage interval. Effect time — plasma concentration data were submitted to nonlinear regression analysis, which showed that the observed BP effects could be dissociated into depressor and pressor components. A window for the antihypertensive effect was established. At a plasma clonidine concentration of 0.65±0.07 ng/ml 50% of the maximal depressor effect was found, and it was only separated by a factor of 2 from the half maximal pure pressor concentration in plasma. No relationship between the change in heart rate and the plasma clonidine was observed. The findings strengthen the importance of close monitoring of clonidine therapy.
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  • 69
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    European journal of clinical pharmacology 26 (1984), S. 381-388 
    ISSN: 1432-1041
    Keywords: midazolam ; hypnotic drug ; benzodiazepine ; pharmacokinetics ; aged patients
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg−1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (± SD) elimination half-life (2.14±1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (± SD) clearance value (0.30±0.19 l kg−1h−1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean ± SD) did not differ to a statistically significant extent between the aged subjects (0.77±0.47 l kg−1) and the young subjects studied previously (1.09±0.58 l kg−1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F=0.59±0.15, mean ± SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34±0.17, (mean ± SD), with an appreciable but variable lag time (0.74±0.40 h, mean ± SD). Orally, in the dose used, the drug was an inefficient hypnotic with four of the six subjects failing to attain the plasma drug level of 44–50 µg l−1, which appeared to be the approximate threshold for sleep. It is impossible to know whether this failure represents an age related effect on drug absorption, or is a consequence of the upper alimentary tract abnormalities for which the endoscopies were done.
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  • 70
    ISSN: 1432-1041
    Keywords: cefoxitin ; beta-lactam antibiotics ; pharmacokinetics ; serum concentration ; pleural fluid concentration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2–3fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.
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  • 71
    ISSN: 1432-1041
    Keywords: cefoperazone ; peritoneal dialysis ; pharmacokinetics ; terminal renal failure ; peritonitis
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoperazone after i.p. and/or i.v. administration were studied in 12 CAPD patients. After i.v. injection, the plasma half-life was 2.65±0.4 h, the total clearance amounting to 70.1±19.2 ml/min. Peritoneal clearance was calculated to be 6.9±1 ml/min. After peritoneal instillation, the bioavailability was 63.9±5%. After repeated i.p. administration, no accumulation of the drug in the body was observed. Thus, cefoperazone can be safely administered for the treatment of peritonitis in CAPD patients.
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  • 72
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    European journal of clinical pharmacology 26 (1984), S. 651-653 
    ISSN: 1432-1041
    Keywords: prednisolone ; prednisone treatment ; pharmacokinetics ; individual variation ; microsomal enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eleven patients on long-term prednisone treatment were studied on two occasions separated by 45 to 325 days. In 10 patients the total body clearance of prednisolone only changed about 10%. In one case a 78.5% decrease was observed after stopping treatment with rifampicin and isoniazide. No association was found between the prednisone dose rate (mg/kg per month), patient age or mean endogenous plasma hydrocortisone level and prednisolone clearance/kg. The results indicate considerable intra-individual consistency of prednisolone kinetics if other conditions are not changed.
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  • 73
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    European journal of clinical pharmacology 26 (1984), S. 749-752 
    ISSN: 1432-1041
    Keywords: dextropropoxyphene ; pharmacokinetics ; half-life ; 3-compartment model ; steady state prediction ; plasma levels
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Data from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5–10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15–30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.
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  • 74
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    European journal of clinical pharmacology 27 (1984), S. 105-110 
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
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  • 75
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    European journal of clinical pharmacology 27 (1984), S. 159-163 
    ISSN: 1432-1041
    Keywords: endralazine ; renal impairment ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11–52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (βt1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in βt1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest βt1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute βt1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.
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  • 76
    ISSN: 1432-1041
    Keywords: sotalol ; hydrochlorothiazide ; pharmacokinetics ; moderate renal failure
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.
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  • 77
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    European journal of clinical pharmacology 27 (1984), S. 583-587 
    ISSN: 1432-1041
    Keywords: propranolol ; pregnancy ; beta-adrenoceptor antagonist ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Propranolol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32 and 36 weeks gestation and when at least 6 weeks postparum. On both occasions, subjects were given propranolol 120 mg orally or 10 mg intravenously in randomised order with a minimum washout period of 1 week. Propranolol was assayed in plasma by gas-liquid chromatography with electron-capture detection and the pharmacokinetic parameters were investigated. There were no significant alterations in elimination half-life, clearance or apparent volume of distribution per kilogram antenatally compared with postnatally: bioavailability was also unchanged. It is concluded that the disposition of propranolol is not altered during pregnancy.
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  • 78
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    Keywords: Bezitramide ; oral absorption profile ; pharmacokinetics ; male volunteers ; experimental pain ; biliary excretion in rats
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oral absorption of bezitramide 5 mg was studied in 7 human volunteers, using a specific radioimmuno-assay which measured both bezitramide and its active metabolite R-4618. A lag time of 0.5–1.0 h and a Cmax of 5.4 ng/ml plasma were found, the latter occurring 2.5–3.5 h after administration. The apparent elimination half-life varied from 11 to 24 h. Less than 0.3% of the dose was excreted unchanged in the urine. High concentrations in the faeces of some individuals indicate incomplete absorption and/or biliary secretion. The analgesic effect, using a standardized superficial electrical stimulation method, reached its maximum between 2.5 and 3.5 h after dosing, in accordance with the absorption phase. The duration of the effect was highly variable. Experiments in rats (n=6,3H-bezitramide 2.5 µg), demonstrated extensive biliary excretion (up to 70% of total radioactivity) and less than 3% of the label was removed by urinary excretion.
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  • 79
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    European journal of clinical pharmacology 11 (1977), S. 149-154 
    ISSN: 1432-1041
    Keywords: Hydroflumethiazide ; spectrofluorometry ; pharmacokinetics ; plasma half life ; renal excretion ; renal disease
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A spectrofluorometric method for determination of hydroflumethiazide in human plasma and urine has been developed. The limit of detection was 10 ng/ml plasma and 100 ng/ml urine. The plasma concentration of hydroflumethiazide was determined for 9–11 hours and excretion in urine for 24–37 hrs after oral administration of about 1 mg/kg body weight to 7 subjects. Plasma half life in healthy subjects was 1.9–2.1 h, and 2.7–8.6 h in patients during the period 4–9 hrs after dosing. Cumulative excretion in urine was 67–79% of the dose during 31–37 hrs in 6 subjects; one patient with renal disease was found to excrete only 25.8% of dose during 24 hours. Renal clearance of hydroflumethiazide was higher in the healthy subjects (0.29–0.44 1 h−1 kg−1) than in the patients (0.040–0.15 l h−1 kg−1). Plasma half life of hydroflumethiazide was not closely correlated with renal clearance of the drug, which suggests that other factors may play a role in determining plasma half life.
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  • 80
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    European journal of clinical pharmacology 16 (1979), S. 243-249 
    ISSN: 1432-1041
    Keywords: timolol ; beta blockade ; pharmacokinetics ; pharmcodynamics ; acute administration ; chronic administration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effects of various oral doses of timolol administered either acutely or after chronic medication for 7 days were studied in healthy volunteers. After acute administration of timolol maximum plasma concentrations were attained within 1–2 h and thereafter declined exponentially with time. The mean apparent half-life of elimination from plasma was 2.5 h and was independent of dose. Area under the plasma concentration-time curve (AUC) was proportional to the orally administered dose. Plasma concentrations, apparent elimination half-life and AUC were not altered after one week of chronic administration. The effect of timolol on heart rate and blood pressure response to three sequentially increasing ‘steady state’ work loads were studied. After acute administration of timolol maximum reduction of systolic blood pressure, resting heart rate, and the different parameters of the work-heart rate (or blood pressure) relationships were produced by 5 mg timolol. Increasing the dose prolonged the duration over which these variables were reduced. The relationship between timolol plasma concentration and inhibition of different parameters of the exercise response was hyperbolic with half maximum inhibition at concentrations of about 3–4 ng/ml of timolol and maximum inhibition above 30 ng/ml. Maximum drug effects and duration of action of timolol on the different variables were similar after acute and chronic administration.
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  • 81
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    European journal of clinical pharmacology 16 (1979), S. 263-270 
    ISSN: 1432-1041
    Keywords: diazepam ; alcoholic beverages ; plasma level ; pharmacokinetics ; co-ordination skills ; red wine ; white wine ; whisky
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty paid healthy students ingested diazepam 10 mg 30 min after the administration of ethanol 0.8 g/kg. The alcoholic beverage used was varied in randomized double-blind experiments, which were repeated at one-month intervals. Psychomotor performance, plasma diazepam, and alcohol concentration in breath were measured 30, 60, 90 min and 2, 3, 4, 6 and 24 h after the ingestion of diazepam. Beer and white wine elevated the plasma level of diazepam and the effect lasted for up to 2 h. Whisky elevated the diazepam level for 90 min. Red wine did not affect it significantly. The alcohol-diazepam combination impaired tracking skills and oculomotor co-ordination and enhanced nystagmus, more than diazepam alone. Red wine produced a breath alcohol concentration higher than after white wine. More nystagmus was recorded after red wine and diazepam, although white wine led to a higher plasma diazepam concentration. It appears that simultaneous ingestion of alcohol and diazepam accelerates the absorption of diazepam. This pharmacokinetic alteration may not contribute much to the combined psychomotor effects of diazepam and alcohol, which were mainly due to pharmacodynamic interaction at receptor level.
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  • 82
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    European journal of clinical pharmacology 16 (1979), S. 271-277 
    ISSN: 1432-1041
    Keywords: lithium ; litarex ; single dose ; multiple dose ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An analysis of the single and multiple dose pharmacokinetics of lithium in 7 healthy volunteers is presented. A solution of lithium chloride was administered in single dose experiments and the same solution and a sustained release preparation were employed in multiple dose experiments, which were carried out at steady state. A fixed dose of 24 mmol was used in the single dose experiments and in the subsequent multiple dose experiments in the same subjects the same dose was administered once daily for a week. Distinct two-compartment characteristics were found, with a mean disposition rate constant (β) of 0.035 h−1±0.010 SD, corresponding to a mean biological half-life of about 19.8 h. The mean half-time of the distributory α-phase was about 1.15 h. The absorption of lithium from an orally administered solution took place with a half-time of about 0.15 h in the single dose experiments. The apparent volume of distribution of the central compartment (Vc) was 0.307 1 kg−1±0.046 SD, less than half that of Vde at equilibrium. Vdβ (Vdarea) was 0.8291 kg−1±0.184 SD and mean total body clearance was 27.6 ml kg−1 h−1±4.7 SD.
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  • 83
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    European journal of clinical pharmacology 16 (1979), S. 255-262 
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; fluorimetry ; high performance liquid chromatography ; linear kinetics ; saturation kinetics ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In Study I 20 normal volunteers received a single oral dose of spironolactone 100 mg. In Study II a further 20 normal volunteers were given first spironolactone 100 mg b.i.d. and subsequently spironolactone 100 mg once a day for a further 4 days. In Study III 5 normal subjects were given a single dose of spironolactone 500 mg. The concentration of canrenone in serum was determined both by fluorimetry and HPLC for 0–48 h in Study I, 120–168 h in Study II and 0–36 h in Study III. The total AUCs after the single 100 mg dose did not differ from the AUCs within the dosing interval during steady state. The half-lives of the terminal log-linear phases were almost identical (14.99±0.80 h and 15.69±0,80 h) when determined by fluorimetry, and were sligthly, but significantly (p〈0.01), longer when determined by HPLC — 20.14±1.62 and 18.71±1.04. The mean ratio of the specific AUC determined by HPLC and the fluorimetrically determined AUC was 0.3 after the single 100 mg dose. It did not differ from the corresponding value during steady state (0.34). In contrast, the ratio after the single 500 mg dose was approximately 50% higher. Fluorimetrically determined AUCs after 100 and 500 mg doses did not show dose-proportionality in contrast to the HPLC-determined AUCs. It was concluded that Canrenone contributes much less to the conventional fluorimetric determination than was previously assumed. It may not provide more than 1/10 and 1/4 of the antimineralocorticoid activity of spironolactone after single dose and multiple doses, respectively. Whereas linear kinetics apply after single and multiple 100 mg doses of spironolactone, after 500 mg saturation kinetics must be assumed with respect to metabolism. Thus, in bioavailability studies high doses of spironolactone should be avoided. For such studies the fluorimetric assay seems to be the appropriate bioanalytical method in spite of its lower specificity.
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  • 84
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    European journal of clinical pharmacology 12 (1977), S. 355-357 
    ISSN: 1432-1041
    Keywords: Nitrazepam ; placental transfer ; pharmacokinetics ; plasma levels ; protein binding
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six women from 14 to 17 weeks pregnant, and 12 woman from 36 to 40 weeks pregnant, were given nitrazepam 5 mg orally about 12 h before legal abortion by hysterotomy in the former group and elective caesarean section in the latter group. The concentration of nitrazepam was determined by gas-liquid chromatography. Binding to plasma proteins was evaluated by separation of the protein-free fraction by ultracentrifugation. In the first group (early pregnancy) the level of nitrazepam was found to be lower in the fetal than in the maternal circulation. The concentration in amniotic fluid was still lower. In the latter group (late pregnancy) the concentration both of unbound and total nitrazepam in maternal and fetal plasma were in equilibrium, which indicated an increase in transplacental transfer in late pregnancy. The percentage of unbound nitrazepam in both cases was 12%.
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  • 85
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    European journal of clinical pharmacology 12 (1977), S. 383-386 
    ISSN: 1432-1041
    Keywords: Benzodiazepine ; temazepam ; pharmacokinetics ; bioavailability ; hard and soft gelatine capsules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels of temazepam were determined in healthy subjects after single oral administration of soft and hard gelatin capsules, and after 7 consecutive night-time doses in soft capsules. Absorption from soft gelatin capsules was significantly faster and produced earlier and higher peak plasma levels. The two pharmaceutical forms did not show any significant difference in relative availability. The apparent half-life of temazepam after night-time administration was significantly shorter than after morning administration, but no change in half-life was observed between the first and seventh night-time doses.
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  • 86
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    European journal of clinical pharmacology 13 (1978), S. 41-48 
    ISSN: 1432-1041
    Keywords: Furosemide ; pharmacokinetics ; anephric patients ; metabolism ; protein binding
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of furosemide 40 mg i.v. were compared in 7 anephric patients and in 7 normal subjects. The average serum clearance was 66 ml/min in the patients and 219 ml/min in the normal subjects, and the corresponding weight corrected clearances were 1.33 ml/min · kg and 2.96 ml/min · kg. Binding to serum proteins was significantly decreased in the anephric subjects, in whom a significant negative correlation was found between the percentage binding and the volume of distribution VDss. In the patients, but not in the normal subjects, there was a significant positive correlation between $$V_{D_{ss} } $$ and serum clearance. Both in normal and anephric individuals 4-chlor-5-sulphamoylanthranilic-acid (CSA) was found, but there was no evidence of special accumulation either of CSA or anthranilic acid in the anephric patients. In the patients the initial increase in serum concentration of sodium and protein followed by a more conspicuous decrease were more pronounced, but none of the changes were statistically significant.
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  • 87
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    European journal of clinical pharmacology 12 (1977), S. 387-392 
    ISSN: 1432-1041
    Keywords: Digoxin ; β-methyldigoxin ; prolonged administration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy volunteers received digoxin 0.4 mg or β-methyldigoxin 0.4 mg i. v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and β-methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54±0.31 days was significantly shorter than the half life of 2.29±0.34 days for β-methyldigoxin. The distribution volume of 807±187 liters for digoxin was not significantly larger than the 735±227 liters for β-methyldigoxin. Renal digoxin clearance of 191±25 ml/min was significantly higher than both the renal clearance of β-methyldigoxin of 111±23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of β-methyldigoxin injected once a day, which was significantly higher than the 1.8-fold accumulation of digoxin.
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  • 88
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    European journal of clinical pharmacology 12 (1977), S. 451-456 
    ISSN: 1432-1041
    Keywords: Bioavailability ; carbamazepine ; elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters:k abs =0.176±0.209 h−1;k=0.0203±0.0055 h−1; T1/2=37.5±13.1 h; VD=0.825±0.1041 · kg−1; Clearance=0.0163±0.0061 l · kg−1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.
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  • 89
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    European journal of clinical pharmacology 13 (1978), S. 29-33 
    ISSN: 1432-1041
    Keywords: Microcrystalline theophylline ; chronic obstructive airways disease ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV1 were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUCss/AUC1, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV1 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.
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  • 90
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    European journal of clinical pharmacology 13 (1978), S. 365-371 
    ISSN: 1432-1041
    Keywords: Etidocaine ; pharmacokinetics ; metabolism ; neonate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The urinary elimination of etidocaine and several of its metabolites was investigated in neonates whose mothers had received one or more doses of etidocaine during labour. The urine collection period ranged among the neonates from 21.4 to 47.0 h post-partum. The total amounts of etidocaine and its metabolites recovered in neonatal urine represented a mean of 0.12 per cent of the maternal dose. Some differences in the pattern of urinary metabolites were observed between neonates and adults. Mean half-life of elimination of etidocaine calculated from sigma-minus plots of the neonatal urinary data was 6.42 h. This is greater than that previously reported following intravenous administration of etidocaine to adults (2.6 h). The slower rate of elimination in neonates is probably due to an increased neonatal volume of distribution since there is evidence to show that etidocaine is extensively metabolised by the neonate.
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  • 91
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    European journal of clinical pharmacology 13 (1978), S. 379-383 
    ISSN: 1432-1041
    Keywords: Antipyrine ; pharmacokinetics ; phenzone ; posture ; immobilization
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single dose of phenazone was studied in six subjects while ambulant and during bed rest for 3 days. Elimination of the drug was followed for 12 h after oral and intravenous administration. The elimination rate constant and total body clearance were significantly increased during bed rest as compared to the ambulant period, but the differences were small. The apparent volume of distribution decreased significantly. No consistent change due to bed rest was found in the rate of absorption or bioavailability of the oral dose.
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  • 92
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    European journal of clinical pharmacology 13 (1978), S. 209-212 
    ISSN: 1432-1041
    Keywords: Paracetamol ; acetaminophen ; Gilbert's syndrome ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of paracetamol after intravenous and oral administration has been studied in 6 patients with Gilbert's syndrome, and 6 healthy controls. Paracetamol clearance was significantly less in the patients (255 ml/min SE±23 ml/min) than in the normal subjects (352 ml/min SE±40 ml/min). Moreover, whilst paracetamol concentrations declined monoexponentially in the patients, the decline was biexponential in the controls. No difference in the bioavailability of 500 mg paracetamol given orally was observed between the two groups. The results suggest that not only is paracetamol elimination impaired in Gilbert's syndrome, but that its distribution kinetics are also abnormal. Both these findings could be attributed to a decrease in hepatic glucuronyl transferase activity.
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  • 93
    ISSN: 1432-1041
    Keywords: Aminopyrine ; pharmacokinetics ; 14CO2 breath test ; hepatic disease
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-course of aminopyrine in plasma and of14CO2 in breath was determined for 6 hours after oral administration of (14C-methyl) aminopyrine to healthy controls and to patients with hepatitis and hepatic fibrosis, cirrhosis and hepatic bilharziasis.14CO2 in breath declined about 1.8 times more slowly than aminopyrine plasma levels, which suggests the occurrence of metabolite demethylation. This was confirmed by the slow elimination of14C from plasma, the formation of14CO2 after aminopyrine had disappeared and the presence of a considerable amount of monomethyl-aminopyrine in plasma. The mean14CO2 concentration in breath was correlated with but was not proportional to aminopyrine clearance, which was attributed to individual differences in aminopyrine half-life. Both a correlation and proportionality were found when14CO2 extrapolated to zero time was used as a parameter of14CO2 production. Hepatic disease affected aminopyrine clearance to a variable extent. In the hepatitis and fibrosis group, aminopyrine clearance was affected in 2 out of five subjects. In all except one cirrhotic subject aminopyrine clearance was markedly decreased. Moreover, in three out of seven cases aminopyrine absorption was impaired, presumably due to decreased gastrointestinal blood-flow. This may produce an erroneously low14CO2 concentration in breath during the first two hours after aminopyrine administration. Hepatic bilharziasis was accompanied by very low aminopyrine clearance in all four cases. In two patients high apparent Vd values were observed, probably due to “first-pass” metabolism. Patients with ascites had Vd values within normal limits.
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  • 94
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    European journal of clinical pharmacology 14 (1978), S. 57-67 
    ISSN: 1432-1041
    Keywords: Chemotherapy ; sulfadiazine ; trimethoprim ; pharmacokinetics ; acetylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sulfadiazine (SDZ) 800 mg and trimethoprim (TMP) 160 mg were given orally to 10 normal subjects and the concentration of SDZ and TMP in serum and urine was followed for 24 h. Both drugs showed a significant negative correlation between individual “peak” concentrations in serum and the body weight of the subject. Twelve hours after dosing the serum concentration was 12 to 25 µg/ml for SDZ and 0.3 to 1.1 µg/ml for TMP. Individual concentration ratios between SDZ and TMP in serum were 4.8 (1 h) – 145 (24 h), and in the urine the ratio was close to 6 throughout the 24 h collection period. The range of urinary concentrations was from 65 to 400 µg/ml for SDZ and from 13.8 to 93.4 µg/ml for TMP. The fraction acetylated SDZ/acetylated SDZ + SDZ was 21% during the 0–8 h period, 33% during the 8–15 h period and 41% during the 15–24 period. The average values for the notional volume of distribution, Vd, were 0.36±0.13 1/kg for SDZ and 1.39±0.25 1/kg for TMP. The average “t1/2” was 15.2±7.4 h for SDZ and 7.4±1.9 h for TMP. Individual subjects showed a significant correlation between the serum clearance of TMP and SDZ (p〈0.01) and also between the renal clearance of the two drugs (p〈0.05). The serum clearance was significantly correlated with the renal clearance for TMP but not for SDZ. For SDZ Vd was significantly negatively correlated with the elimination constant; for TMP no such correlation was found. The serum clearance of SDZ was significantly correlated with the percentage of SDZ which was excreted as the (presumably) acetylated compound. The renal clearance of SDZ was independent of the serum concentration of SDZ. There was a highly significant negative correlation between the renal clearance and serum concentration of TMP, as well as for “acetylated SDZ”. The renal clearance of “acetylated SDZ” averaged more than six times that of unconjugated SDZ. With increased urine flow the renal clearances of TMP and SDZ were significantly increased.
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    European journal of clinical pharmacology 14 (1978), S. 237-244 
    ISSN: 1432-1041
    Keywords: Furosemide ; arterial hypertension ; protein binding ; sodium excretion ; renal function ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 40 mg was injected intravenously in 7 patients with severe hypertension and vascular complications. A two compartment, open model was used to describe the disappearance of the drug from serum. The mean serum clearance (Cls=1.83 ml/min · kg) was significantly reduced compared to the mean Cls-value of a group of normals (2.96 ml/min · kg). A significant correlation was found between Cls and mean blood pressure, as well as between Cls and renal clearance (mean Clr=0.83 ml/min · kg); extrapolation of the regression line yielded a Cls-value of 50 ml/min for Clr=0. The Clr was also significantly negatively correlated with mean blood pressure. Protein binding of furosemide was normal, except in one patient, who had considerable impairment of renal function. Apparently more than 90% of unchanged furosemide passed in urine was excreted by tubular transport. A highly significant negative correlation was found between Cls and the fraction of furosemide excreted as a glucuronide. During the first two hours, significantly less sodium was excreted by the patients than by a comparable group of normal subjects. The correlation between serum concentration of furosemide and the amount excreted of sodium was not significant, but highly significant correlations were found between the amounts of furosemide and sodium excreted by the kidney in 0–30 and 0–60 min. In all the individual patients an approximately linear relationship with wide variation in the slope was found between the cumulative excretion of furosemide and sodium from 0–30 min to 0–60 and to 0–120 min. After 120 min deviations were observed in the curves from 4 of the patients, which indicated that smaller and smaller additional amounts of sodium were excreted with constant additional amounts of furosemide.
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  • 96
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    European journal of clinical pharmacology 14 (1978), S. 267-271 
    ISSN: 1432-1041
    Keywords: Lithium ; sustained-release ; pharmacokinetics ; manic patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An ordinary and a sustained-release lithium carbonate preparation were administered acutely at equivalent dosage (1.80 g=24.3 mmol) in a crossover fashion to manic patients. Serum lithium levels were determined by atomic absorption spectroscopy and pharmacokinetic parameters were calculated. Maximum mean serum levels of 1.13 mmol/l and 0.78 mmol/l were achieved at 6 h and 12 h respectively with the ordinary and sustained-release forms. The mean half-lives of absorption, redistribution and elimination were 0.78 h±0.05 (SE), 5.06 h±0.23, 26.8 h±4.5 and 3.73 h±0.37 (SE), 4.42 h±0.28 and 25.6 h±5.5 for the ordinary and sustained-release forms respectively. In healthy volunteers the ordinary preparation was completely absorbed but only 85% of the sustained-release form was absorbed in the manic subjects. Lithium ion distributed into two kinetic compartments and the final compartment appeared to correspond to total body water.
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  • 97
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    European journal of clinical pharmacology 14 (1978), S. 277-280 
    ISSN: 1432-1041
    Keywords: Doxycycline ; iron ; charcoal ; enteral cycling ; man ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to study the intestinal interactions of doxycycline (DC) with Fe++ and charcoal, two groups of healthy volunteers were given either 200 mg or 100 mg DC in capsules at 2 p. m. and 9 p. m., and blood samples for fluorimetric assay of DC were collected for 24 h starting at 8.30 a. m. on the following morning. A 24-h-urine was also collected. The test was subsequently repeated at one-week intervals, when the volunteers also ingested either ferrous sulphate (80 mg Fe++) or charcoal (4.0 g) immediately after the zero-time sample of DC and at 3, 8 and 12 h. Charcoal completely adsorbed DC in vitro in an artificial small intestinal fluid. Ferrous sulphate or charcoal did not modify the serum level or urinary excretion of DC after the 200 mg+200 mg dose, but ferrous sulphate did reduce the 24-h urinary excretion of DC after the 100 mg+100 mg dose. The serum half-life and AUC of DC were reduced by ferrous sulphate given after the 100 mg+100 mg dose of DC. Charcoal did not modify any parameter, even after the 100 mg+100 mg dose of DC. The results do not support existence of important enteral cycling of DC. Although oral ferrous sulphate can lower the serum level and shorten the serum half-life of DC, the acute experiment suggested that a therapeutic serum level of DC can be maintained despite treatment with iron in the doses used in iron-deficiency, and charcoal in the doses used in diarrhoeic states, if the drugs are administered several hours apart.
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  • 98
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    European journal of clinical pharmacology 15 (1979), S. 187-192 
    ISSN: 1432-1041
    Keywords: quinidine ; plasma protein binding ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant (β) varied from 0.071 to 0.146 h−1 (mean 0.113), and apparent volume of distribution (Vβ) varied from 1.39–3.20 l · kg−1β (mean 2.27). Total body clearance was 2.32–6.49 ml min−1 · kg−1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both Vβ (r=0.885, p〈0.01) and total body clearance (r=0.668, p〈0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.
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  • 99
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    European journal of clinical pharmacology 14 (1978), S. 69-73 
    ISSN: 1432-1041
    Keywords: Citalopram ; pharmacokinetics ; man ; steady state levels ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of citalopram, a potent serotonin reuptake inhibitor, and its demethylated metabolite have been determined by a specific fluorescence coupling technique during single dose experiments in volunteers and in clinical tests. Citalopram was found to have linear kinetics within the dose range investigated, which were characterized by fairly rapid absorption and slow elimination (biological half-life 1–21/2 days). Steady state levels in the range 120–340 nM (i.e. slightly above those associated with pharmacodynamic activity in animals) were attained within a week. A drug/metabolite ratio of 2–3 was recorded.
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  • 100
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    European journal of clinical pharmacology 19 (1981), S. 65-71 
    ISSN: 1432-1041
    Keywords: atenolol ; haemodialysis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of atenolol were determined following acute intravenous and chronic oral administration to 20 subjects with a glomerular filtration rate (GFR) between 5 and 113 ml/min. Plasma levels in a further 5 patients on haemodialysis were measured after intravenous treatment. The mean half life of elimination increased from 5.9 h in patients with normal renal function to 42.1 h in preuraemic patients (GFR 〈10 ml/min) following a single i. v. dose. The half life of elimination following chronic oral administration was not significantly different. Mean peak plasma concentrations increased from 540 ng/ml in patients with normal renal function to 1493 ng/ml in preuraemic patients following chronic oral treatment with 100 mg/day. The mean half life of elimination during a single haemodialysis treatment was 4.3 h. In patients with a GFR 〉30 ml/min the normal daily dose of atenolol should be employed, in patients with a GFR between 10 and 30 ml/min the dose should be reduced by half, and in patients with a GFR 〈10 ml/min a reduction by three quarters of the normal dose is recommended.
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