Isomeric inversion of ibuprofen (r)‐enantiomer in humans

Kaiser, David G.; Vangiessen, Garrett J.; Reischer, Robert J.; Wechter, William J.

doi:10.1002/jps.2600650222

Cited by 191 publications

(72 citation statements)

References 5 publications

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“…This difference might be significant as the 95% confidence intervals do not overlap. In infants, the plasma concentrations of the S(+) isomer were significantly lower than those of the R(-) form, while in adults the S(+) isomer predominates [2,3,5,14]. Explanations for this difference include impaired R to S inversion in the infant, and/or a higher clearance of the S enantiomer.…”

Section: Resultsmentioning

confidence: 99%

“…Its pharmacological activity with respect to cyclooxygenase inhibition is thought to reside almost exclusively in the S(+) configuration [1]. The disposition of this drug is stereoselective, the difference being due mainly to unidirectional metabolic inversion of the R(-) to the S(+) isomer [2]. The differential kinetics of the individual enantiomers have been studied in adults [3][4][5] but not in children.…”

Section: Introductionmentioning

confidence: 99%

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Stereoselective disposition of ibuprofen enantiomers in infants.

Lee

Williams

Day

et al. 1994

Brit J Clinical Pharma

108

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The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 +/‐ 0.3 mg kg‐1 dose of the racemate in 11 infants. Mean (+/‐ s.d.) half‐lives were 1.6 +/‐ 0.5 h for S(+) and 1.5 +/‐ 0.5 h for R(‐) and mean (+/‐ s.d.) AUC values were 31.5 +/‐ 14.3 mg l‐1 h for S(+) and 36.6 +/‐ 13.8 mg l‐1 h for R(‐). Since plasma concentrations of the active S(+)‐isomer were lower than those reported in adults, a higher dosage might be required in infants.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stereoselective disposition of ibuprofen enantiomers in infants.

Lee

Williams

Day

et al. 1994

Brit J Clinical Pharma

108

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“…(A direct test of this assumption is currently under way in our laboratory.) Racemization of Ibuprofen was shown to occur in vivo (Kaiser et al, 1976), at the stage of the coenzyme A thioester (Knihinicki et al, 1989;Chen et al, 1991) and is of importance pharmacologically (Adams et al, 1976). The enzyme believed to be responsible was recently purified from rat liver by Shieh and Chen (1993) as '2-arylpropionyl-CoA racemase'.…”

Section: Discussionmentioning

confidence: 99%

Purification and properties of an α‐methylacyl‐CoA racemase from rat liver

Schmitz

Fingerhut

Conzelmann

1994

European Journal of Biochemistry

105

134

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The (R)-and (S)-isomers of a-methyl-branched fatty acids were shown to be rapidly interconverted as coenzyme A thioesters, by an a-methylacyl-CoA racemase. The enzyme was purified some 5600-fold from rat liver, to apparent homogeneity. It is a monomer of 45 kDa with an isolectric point of pH 6.1 and is optimally active between pH 6 and pH 7. It acts only on coenzyme A thioesters, not on free fatty acids, and accepts as substrates a wide range of a-methylacyl-CoAs, including pristanoyl-CoA and trihydroxycoprostanoyl-CoA (an intermediate in bile acid synthesis), but neither 3-methyl-branched nor linear-chain acyl-CoAs. The racemase catalyzes a rapid exchange of the H atom in the a-position of the fatty acid against a proton from water, indicating that the mechanism involves abstraction of a proton. Based on this observation, a very sensitive and convenient radiometric assay, with 2-methy1[2-3H]acyl-CoAs as substrates, was developed. The enzyme was inactivated by micromolar concentrations of Hg2' and to a lesser extent by Cu2+ but not by iodoacetamide and only slightly by N-ethylmaleimide and thimerosal.

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“…It should be noted that because of the unidirectional inversion process, the majority of administered racemic ibuprofen is excreted as metabolites of the S(+)-enantiomer (Mills et al, 1973;Kaiser et al, 1976). Because ibuprofen's spectrum of adverse reactions includes gastrointestinal side-effects (Fowler et al 1980), concurrent administration with anti-ulcer drugs, such as the histamine H2-receptor antagonist cimetidine, is not uncommon.…”

Section: Introductionmentioning

confidence: 99%

Lack of effect of cimetidine on the pharmacokinetics of R(−)− and S(+)‐ ibuprofen.

Evans

Nation

Sansom

1989

Brit J Clinical Pharma

280

504

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1 To investigate the effect of cimetidine on the pharmacokinetics of R(-)-and S(+)-ibuprofen, six healthy male volunteers received orally 800 mg racemic ibuprofen both in the drug-free state (control phase, C) and on the second day of a 3 day course of oral cimetidine, 1 g daily (treatment phase, T). The two phases (14 days apart) were randomised in a balanced cross-over manner.2 The plasma concentrations of R(-)-and S(+)-ibuprofen were measured by highperformance liquid chromatography (h.p.l.c.). The protein binding of the enantiomers was assessed in a selection of plasma samples from each volunteer. Following alkaline hydrolysis of glucuronide conjugates, the urinary recoveries of ibuprofen and its major metabolites were measured by h.p.l.c. 3 There was no difference (P > 0.05, two-tailed Student's t-test; data expressed as mean ± s.d.) between C and T phases in the total area under the plasma concentration-time curve of R(-)-ibuprofen (C 4514 ± 1063 mg 1-1 min vs T 4665 ± 1435 mg 1-1 min) and S(+)-ibuprofen (C 6460 ± 1063 mg 1-1 min vs T 6886 ± 1207 mg 1-1 min). Similarly, for each enantiomer, there was no difference between the two phases in the terminal half-life, the maximum plasma concentration or the time of its occurrence. 4 Cimetidine treatment had no effect (P > 0.05) on the time-averaged percent unbound in plasma of R(-)-ibuprofen (C 0.419 ± 0.051% vs T 0.435 ± 0.060%) and S(+)-ibuprofen (C 0.643 ± 0.093% vs T 0.633 ± 0.053%). 5 There was no difference (P > 0.05) in the percentage of the administered dose recovered in the urine as ibuprofen plus metabolites (C 84.9 ± 7.3% vs T 87.6 ± 3.9%). 6 The results indicate that the pharmacokinetics of R(-)-and S(+)-ibuprofen after a single oral dose of racemic ibuprofen were not influenced by concurrent cimetidine administration.

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Isomeric inversion of ibuprofen (r)‐enantiomer in humans

Cited by 191 publications

References 5 publications

Stereoselective disposition of ibuprofen enantiomers in infants.

Stereoselective disposition of ibuprofen enantiomers in infants.

Purification and properties of an α‐methylacyl‐CoA racemase from rat liver

Lack of effect of cimetidine on the pharmacokinetics of R(−)− and S(+)‐ ibuprofen.

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