ALBERT — All Library Books, journals and Electronic Records Telegrafenberg

1

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Pharmacokinetics of S(+)- and R(−)-ibuprofen in volunteers and first clinical experience of S(+)-ibuprofen in rheumatoid arthritis (1990)

Geisslinger, G. ; Schuster, O. ; Stock, K. -P. ; [et al.]

Springer

European journal of clinical pharmacology 38 (1990), S. 493-497

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ISSN: 1432-1041

Keywords: ibuprofen ; rheumatoid arthritis ; enantiomer ; stereoselectivity ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary S(+)-, R(−)- or racemic ibuprofen was administered orally to volunteers in doses of 150 mg, 300 mg and 500 mg pure S(+)-, 300 mg pure R(−)- and 600 mg racemic ibuprofen. The pharmacokinetic parameters in humans showed that S(+)-ibuprofen was not inverted to R(−)-ibuprofen, whereas R(−)-ibuprofen was inverted to S(+)-ibuprofen to a variable degree. S(+)-ibuprofen and R(−)-ibuprofen given alone more rapidly reached significantly higher maximal plasma concentrations than after the same doses of the racemic compound. The elimination half-lives and clearance values for all three forms of ibuprofen were comparable. The mean residence time of S(+)-ibuprofen after R(−)- and racemic ibuprofen was significantly longer than after administration of the pure S(+)-enantiomer. Judged by the AUC, the bioavailability of S(+)-ibuprofen was independent of the dose within the range tested. Administration of S(+)-ibuprofen to 6 rheumatic patients showed that the pharmacokinetic behaviour of S(+)-ibuprofen in patients was similar to that found in volunteers. S(+)-ibuprofen proved to be an effective analgesic antirheumatic drug in the dose range 1 to 1.5 g/day.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02336690

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2

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Rapid Determination of Methadone in Plasma, Cerebrospinal Fluid, and Urine by Gas Chromatography and Its Application to Routine Drug Monitoring (1993)

Schmidt, Norbert ; Sittl, Reinhard ; Brune, Kay ; [et al.]

Springer

Pharmaceutical research 10 (1993), S. 441-444

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ISSN: 1573-904X

Keywords: methadone ; gas chromatography with nitrogen–phosphorus detection ; plasma ; urine ; cerebrospinal fluid

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Determination of methadone (MET) in biological fluids can serve to adjust dosages in patients suffering from cancer pain or participating in methadone maintenance programs. We developed a gas chromatographic assay using nitrogen-phosphorus detection. The method involves a single-step extraction from alkalized plasma, cerebrospinal fluid, or urine into n-hexane/isoamylalcohol (99/1, v/v). Dextropropoxyphene was used as internal standard. Separation was achieved with a silica SE-52-CB column (13 m × 0.25-mm I.D.). The method was validated for the determination of MET in plasma, urine, and cerebrospinal fluid with a quantification limit of 0.5 ng/ mL. The coefficients of variation for within-day and between-day precision were within 10.2 and 14.1%, respectively. Approximately 100 samples can be analyzed by one person in the course of a working day, making the method applicable to routine drug monitoring. The method was demonstrated to be sensitive and accurate for pharmacokinetic studies in plasma, urine, or cerebrospinal fluid.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1018904825958

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3

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Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition (1991)

Brune, K. ; Beck, W. S. ; Geisslinger, G. ; [et al.]

Springer

Cellular and molecular life sciences 47 (1991), S. 257-261

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ISSN: 1420-9071

Keywords: Aspirin-like drugs ; flurbiprofen enantiomers ; anti-inflammatory ; analgesic ; gastrointestinal toxicity ; prostaglandin synthesis ; rat

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Medicine

Notes: Summary Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01958153

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4

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Pharmacokinetics of ibuprofen enantiomers in dogs (1991)

Beck, Winfried S. ; Geisslinger, Gerd ; Engler, Heidrun ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 3 (1991), S. 165-169

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ISSN: 0899-0042

Keywords: ibuprofen ; enantiomer ; stereoselectivity ; chiral inversion ; pharmacokinetics ; dog ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: Inversion of inactive (R)-ibuprofen to active (S)-ibuprofen has been suggested to occur presystemically only. In order to investigate the site of inversion in dogs we administered both enantiomers either intravenously or intraduodenally (10 mg/kg) to adult, male beagle dogs (n = 3) in a crossover design. Plasma, urine, and bile were collected for up to 6 h and analyzed stereospecifically by HPLC, according to a previously published method. Pharmacokinetic parameters were calculated using a linear computer program. Absorption after intraduodenal administration occurred rapidly, resulting in maximum plasma concentrations 0.2 h after giving the enantiomer. Approximately 70% of the (R)-enantiomer (according to AUC) was inverted to the S-enantiomer independent of route of administration. No R-ibuprofen could be detected in plasma after (S)-ibuprofen administration. Mean residence time was found to be 2 to 3 times longer for (S)-than for (R)-ibuprofen. Total systemic clearance from plasma was twice as high for (R)- than for (S)-ibuprofen. There were no differences between plasma clearances after intravenous and intraduodenal administration. Between 8 and 17% of dose was recovered in bile [especially as free and conjugated (S)-ibuprofen] and 3-12% in urine [as (S)-ibuprofen, hydroxy- and carboxyibuprofen, free and conjugated forms]. Small amounts of (R)-ibuprofen were detected in bile after intraduodenal administration of (R)-ibuprofen only (1.8% of dose). In short, the unidirectional inversion of R-ibuprofen appears to occur systemically rather than presystemically in dogs.

Additional Material: 1 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/chir.530030304

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5

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The effect of the enantiomers of ibuprofen and flurbiprofen on the β-oxidation of palmitate in the rat (1992)

Zhao, Bin ; Geisslinger, Gerd ; Hall, Iris ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 4 (1992), S. 137-141

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ISSN: 0899-0042

Keywords: 2-arylpropionic acids ; nonsteroidal antiinflammatory drugs ; stereoselective ; coenzyme A thioesters ; chiral inversion ; oxidative phosphorylation ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: The effects of the enantiomers of ibuprofen (0.25 and 0.50 mmol/kg b.w.) and flurbiprofen (0.01, 0.03, and 0.06 mmol/kg b.w.) on the β-oxidation of palmitate were investigated in the rat. The mean cumulative exhalation of 14CO2 after ip administration of [U-14C]palmitic acid was significantly reduced over 6 h by ibuprofen at the higher dose but not at the lower dose for either enantiomer. There was no difference between the enantiomers, the reduction over 6 h being 31.3 and 33.0% for (R)- and (S)-ibuprofen, respectively. There was also a significant inhibition of β-oxidation by flurbiprofen at all 3 doses. Again, there was no stereoselectivity evident in this inhibition. Flurbiprofen was much more potent than ibuprofen in eliciting this effect, the 0.01mmol/kg dose giving a similar reduction in β-oxidation as observed for the 0.50 mmol/kg dose of ibuprofen. The data support the hypothesis that inhibition of the in vivo β-oxidation of palmitate by ibuprofen and flurbiprofen is primarily via a nonstereoselective noncoenzyme A-dependent mechanism. © 1992 Wiley-Liss, Inc.

Additional Material: 1 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/chir.530040302

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6

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Stereoselectivity of biliary excretion of 2-arylpropionates in rats (1993)

Menzel, Sabine ; Beck, Winfried S. ; Brune, Kay ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 5 (1993), S. 422-427

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ISSN: 0899-0042

Keywords: 2-arylpropionates ; enantiomers ; stereoselectivity ; chiral inversion ; pharmacokinetics ; bile-duct cannulated rats ; biliary excretion ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: To examine the stereoselectivity of biliary excretion, the optically pure enantiomers of ketoprofen (KT), ibuprofen (IBU), and flurbiprofen (FLU) were intravenously administered to normal and bile duct-cannulated rats at 10 mg/kg. The recovery of total KT in bile was significantly higher after administration of (S)-KT than after (R)-KT [90.1 ± 3.5% vs 68.8 ± 8.2%, n =3, P 〈 0.05]. In normal rats the terminal half-life of (R)-KT was significantly shorter than that of (S)-KT after administration of (R)-KT (2.2 ± 0.6 h vs 14.3 ± 4.9 h, n = 3, P 〈 0.05). The terminal half-life of both enantiomers was significantly shorter in rats with continuous bile drainage as compared to normal rats. No significant differences in pharmacokinetic parameters could be found between both enantiomers in bile duct-cannulated animals. The total amount of IBU in bile was slightly higher after administration of (S)-IBU than after (R)-IBU administration. The percentage of (R)-IBU after (R)-IBU administration, however, was very low [(R)-IBU: 1.5 ± 0.9%, (S)-IBU: 23.4 ± 5.8%]. In normal rats the clearance of (R)-IBU was significantly higher as compared to (S)-IBU. Differences in pharmacokinetic parameters between normal and bile duct-cannulated rats were not statistically significant due to high interindividual variability. The total recovery of FLU, which was excreted in bile to a lower extent than either KT or IBU, also tended to be greater after S-enantiomer administration. Only small amounts of (S)-FLU could be recovered in bile after (R)-FLU administration. The pharmacokinetic parameters did not differ significantly between (R)- and (S)-FLU or between normal and bile duct-cannulated rats due to its low inversion rate and low excretion via bile. © 1993 Wiley-Liss, Inc.

Additional Material: 3 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/chir.530050606

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7

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Stereoselective pharmacokinetics of methadone in beagle dogs (1994)

Schmidt, Norbert ; Brune, Kay ; Williams, Kenneth M. ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 6 (1994), S. 492-495

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ISSN: 0899-0042

Keywords: enantiomers ; methadone ; pharmacokinetics ; beagle dog ; iv administration ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: The pharmacokinetics of methadone were studied in beagle dogs (n = 4) following intravenous administration of the racemate (0.5 mg/kg) and of the individual (R)-(0.25 mg/kg) and (S)-enantiomers (0.25 mg/kg) using a stereospecific HPLC assay. There was no significant difference between the pharmacokinetic parameters of (R)-methadone and (S)-methadone following administration of the individual enantiomers. Stereoselective differences were evident following administration of the racemate (P values for differences in AUC and CL were 0.001 and 0.046, respectively) and the clearance of the (S)-enantiomer was increased when administered as part of the racemate (316 ± 81 vs 487 ± 128 ml/min, P = 0.04). The data suggest that stereoselective disposition including potential enantiomer-enantiomer interactions should be considered in pharmacokinetic-pharmacodynamic studies of (R,S)-methadone. © 1994 Wiley-Liss, Inc.

Additional Material: 3 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/chir.530060608

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8

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The Biliary Elimination and Enterohepatic Circulation of Ibuprofen in Rats (1990)

Dietzel, Klaus ; Beck, Winfried S. ; Schneider, Hans-Th. ; [et al.]

Springer

Pharmaceutical research 7 (1990), S. 87-90

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ISSN: 1573-904X

Keywords: nonsteroidal antiinflammatory drugs (NSAID) ; ibuprofen ; pharmacokinetics in rats ; biliary elimination ; enterohepatic cycling

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The biliary and urinary excretion of ibuprofen and its metabolites were determined in rats after intravenous and peroral administration of 25 and 100 mg/kg of the drug. Within 24 hours 48% of the low i.v. dose and 59% of the high i.v. dose were eliminated via bile as ibuprofen and its metabolites. Following oral administration 40 to 41% of the dose were recovered in bile, whereas 16 to 32% of the dose were eliminated in urine, resulting in an overall drug recovery of 66 to 79% within 24 hours. Upon infusion of bile containing ibuprofen and its metabolites into the duodenum substantial enterohepatic cycling of the drug occurred in the rat.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1015847912059

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