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  • 1
    ISSN: 1432-1041
    Keywords: atenolol ; bopindolol ; metoprolol ; oxidation polymorphism ; debrisoquine ; bufuralol ; stereoselective metabolism ; pharmacological effect ; healthy volunteers ; beta-blocker
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten healthy subjects whose genetic oxidative phenotype had been determined (6 extensive and 4 poor metabolizers of the debrisoquine-sparteine type of polymorphism) received single oral doses of 3 beta-blockers: atenolol, bopindolol and metoprolol. The plasma concentrations and the extent of the decrease in exercise-induced tachycardia were determined. The oxidative polymorphism was only significant for substances that had a high hepatic first pass metabolism, such as metoprolol. The metabolic pathway under genetic control was highly stereoselective. This observation must be taken into account when assessing the relation between the plasma concentration and effect of these drugs, which are often administered as racemic mixtures.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 28 (1985), S. 317-320 
    ISSN: 1432-1041
    Keywords: bufuralol ; debrisoquine ; sparteine ; genetic/oxidative polymorphism ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bufuralol is a beta-adrenoceptor blocking drug whose oxidative metabolism is under the same genetic control as debrisoquine and sparteine. The pharmacokinetics of bufuralol were studied in 10 healthy subjects (7 extensive and 3 poor metabolizers of debrisoquine) after oral and intravenous administration. In extensive metabolizers the systemic availability of bufuralol was 43%. Poor metabolizers were characterized by a considerable increase in systemic availability due to a corresponding decrease in hepatic first-pass metabolism. After oral administration of bufuralol non-linear kinetics may occur.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 21 (1981), S. 65-72 
    ISSN: 1432-1041
    Keywords: pindolol ; pharmacokinetics ; renal clearance ; computer fit ; saturable tubular reabsorption ; tubular secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of pindolol have been examined following the administration of single doses of 15 mg tablets to eight healthy male subjects. The apparent half-life of elimination in plasma (t1/2=4.05 h) and in urine (t1/2=3.21 h) was calculated using conventional pharmacokinetic methods. The renal clearance was estimated by plotting urinary excretion rates versus plasma concentrations; for all subjects these plots were curved. In addition to these graphical estimations, the plasma concentrations of pindolol and the urinary excretion data for each volunteer were simultaneously fitted using a one or two-compartment open body model; a computer program using non-linear regression algorithms was used. This procedure did not give an adequate fit to the data. Another type of data analysis, using a population — based model, permitted us to show that the renal elimination of pindolol in man comprises of two separate processes — tubular secretion and reabsorption, which was partially saturable under the experimental conditions. The theoretical relevance and clinical significance of these findings are discussed.
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  • 4
    ISSN: 1432-1041
    Keywords: bufurlol ; pharmacokinetics ; oxidative polymorphism ; hydroxylation polymorphism ; betaadrenoceptor blocking agents ; phenotype ; interindividual variations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oxidative metabolism of bufuralol is under the same genetic control as that of debrisoquine and sparteine. 154 fasting volunteers received a 30 mg tablet of bufuralol and a blood sample was taken 3 h later. In poor metabolizers (8% of the sample) the plasma bufuralol concentrations were very high and the metabolite concentrations were low. The genetic oxidative status is a major source of interindividual variation in the plasma concentration of drugs that undergo oxidative metabolism.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 38 (1990), S. 547-549 
    ISSN: 1432-1041
    Keywords: piroxicam ; tenoxicam ; cholestyramine ; pharmacokinetics ; enterohepatic circulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To assess the extent of enterohepatic recycling of piroxicam and tenoxicam, their pharmacokinetics have been compared in the absence and presence of concomitant treatment with cholestyramine. In a randomized crossover study 6 healthy volunteers received piroxicam and tenoxicam 20 mg p.o., alone or with cholestyramine 24 g/day for 4 days. Cholestyramine increased piroxicam & tenoxicam elimination approximately 2-fold (t1/2 50.3 vs 28.1 h and 73.6 vs 35.8 h, respectively). It also increased the apparent clearance (Cl/f) of piroxicam and tenoxicam by 58% and 112%. When cholestyramine was administered, the t1/2 of piroxicam & tenoxicam were correlated (r=0.89), which suggests that their hepatic biotransformation is under a common control. It is concluded that: piroxicam and tenoxicam are eliminated to a large and comparable extent through the biliary route, and the administration of cholestyramine may help to accelerate their elimination in cases of overdosage.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 41 (1991), S. 573-578 
    ISSN: 1432-1041
    Keywords: Midazolam ; drug metabolism ; cytochrome P-450 ; P-450 IIIA ; drug interaction ; adverse effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The biotransformation of midazolam is mediated by a cytochrome P-450 isozyme (P-450 IIIA) whose activity is highly variable. The kinetics of the 1′- and 4-hydroxylation of midazolam, the major routes of midazolam oxidation, by human liver microsomes have been examined to characterize further the cytochrome isozyme(s) catalysing these reactions, and to screen for drugs that might interfere with them. In hepatic microsomal preparation from two kidney donors (extensive and poor metabolisers of debrisoquine) KM values for 1′-hydroxylation were 4.2 and 6.1 μM (extensive and poor metabolisers, respectively), and for the 4-hydroxylation they were 14.7 and 18.1 μM, respectively. The corresponding Vmax values were 25.8 and 29.8 and 17.0 and 18.1 nmolsdmg P−1·h−1. Both reactions appeared to be catalysed by the same or by coregulated isozymes. Midazolam hydroxylations in vitro are inhibited by many drugs, including nifedipine and other dihydropyridine-type calcium channel blockers, ergot alkaloids, cyclosporine, erythromycin and phenothiazine-type neuroleptics. A clinical case report illustrates the consequence of such a drug-drug interference with hepatic biotransformation; midazolam-induced sleep in a patient lasted for 6 days (t1/2=25 h).
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  • 7
    ISSN: 1432-1041
    Keywords: bufuralol ; hepatic oxidation ; debrisoquine/sparteine phenotype ; stereo- and regioselectivity ; metabolites ; healthy volunteers ; drug metabolism ; polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of the debrisoquine/sparteine-type of oxidation polymorphism on plasma bufuralol concentration and the pattern of urine metabolites was studied in extensive and poor metabolizer subjects. (+)- and (−)-bufuralol, and (+)- and (−)-OH-bufuralol in plasma were determined by enantioselective HPLC, and urinary bufuralol and its metabolites were assayed by gas chromatography-mass spectrometry. Three hours after administration of racemic bufuralol the plasma (−)/(+) isomeric ratio for unchanged bufuralol was 1.84 in extensive metabolizers, indicating preferential clearance of the (+)-isomer through aliphatic 1′-hydroxylation and glucuroconjugation, while the (−)-isomer was mainly eliminated by aromatic 4-hydroxylation. Poor metabolizers were characterized by impaired 1′- and 4-hydroxylation, with almost total abolition of the stereoselectivity of these reactions. The data strongly suggest that both 1′- and 4-hydroxylation are catalyzed by the same enzyme. These in vivo observations are in agreement with recent in vitro data obtained in human liver microsomes from phenotyped patients and support the concept of deficiency of a highly stereoselective cytochrome P-450 isozyme as the cause of this polymorphism.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 29 (1986), S. 739-741 
    ISSN: 1432-1041
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 49 (1996), S. 305-308 
    ISSN: 1432-1041
    Keywords: Lornoxicam ; CYP2C9 ; cytochrome-P-450 ; drug metabolism ; NSAIDs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The nature of the enzyme(s) catalysing the biotransformation of lornoxicam to one of its major metabolites, 5′-hydroxy-lornoxicam, has been investigated in human liver microsomes. The reaction kinetics were characterised, the affinity of lornoxicam for three major human drug metabolising cytochrome P-450 isozymes (CYP2C9, CYP2D6 and CYP3A4) was determined, and inhibition of the reaction by known substrates (diclofenac, ibuprofen, mefenamic acid, phenytoin, tolbutamide and warfarin) and the prototype inhibitor (sulphaphenazole) of CYP2C9 was investigated. Results: Lornoxicam 5′-hydroxylation displayed single enzyme Michaelis-Menten kinetics, with a KM of 3.6 μmol·l-1 and a Vmax of 2.6 nmol·h-1·mg-1 microsomal protein. The apparent affinity of lornoxicam was high for CYP2C9, but negligible for CYP3A4 and CYP2D6. Inhibition of lornoxicam 5′-hydroxylation by CYP2C9 substrates and sulphaphenazole was comparable in all livers preparations, values predicted from their KM or Ki for CYP2C9 determined in separate studies assuming competitive inhibition. Sulphaphenazole competitively and completely inhibited lornoxicam 5′-hydroxylation (Ki=0.31 μmol·l-1) as well as lornoxicam clearance (Ki=0.33 μmol·l-1), partial metabolic clearance (fm)=0.95). Conclusion: 5′-Hydroxylation appears to be the only cytochrome P-450 catalysed metabolic reaction of lornoxicam by human liver microsomes and this major in vivo biotransformation pathway is catalysed virtually exclusively by CYP2C9.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 43 (1992), S. 551-553 
    ISSN: 1432-1041
    Keywords: (±)-Nicardipine, Nifedipine, Hypertension ; elderly, pharmacokinetics, pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentration-effect relationships of (±)-nicardipine and nifedipine have been investigated in hypertensive geriatric patients. Following a parallel group, randomised, double blind trial design, they received either slow release nifedipine 20 mg b. d. (n = 9) or slow release (±)-nicardipine 50 mg b. d. (n=10) for 7 days. On Days 1 and 7 serum (±)-nicardipine and nifedipine, blood pressure and heart rate were measured 6 and 12 h after drug administration. (±)-Nicardipine showed significant cumulation (ca 2x) without a corresponding decrease in blood pressure or increase in heart rate. Concentration-effect plots indicated that (±)-nicardipine was more potent than nifedipine but that it showed apparently comparable efficacy in reducing the blood pressure. Compared to young healthy volunteers, both drugs had a more pronounced effect in elderly patients.
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