The metabolic chiral inversion of 2-arylpropionic acids—a novel route with pharmacological consequences

Hutt, Andrew J.; Caldwell, John

doi:10.1111/j.2042-7158.1983.tb02874.x

Cited by 391 publications

(163 citation statements)

References 36 publications

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“…All of the 2-phenylpropionic interesting feature of the disposition of ibuprofen acid derivatives possess a chiral carbon atom and in humans is the stereoselective metabolic as such exist as two mirror image forms, or inversion of the R(-)-enantiomer to the S(+)-enantiomers. Although it is used clinically in its enantiomer (Hutt & Caldwell, 1983). This optical inversion, a phenomenon common amongst 2-phenylpropionic acid derivatives (Hutt & Caldwell, 1983), has been estimated to account for about 63% of the total metabolism of an orally administered dose of R(-)-ibuprofen (Lee et al, 1985) and as such assumes clinical importance.…”

Section: Introductionmentioning

confidence: 99%

“…Although it is used clinically in its enantiomer (Hutt & Caldwell, 1983). This optical inversion, a phenomenon common amongst 2-phenylpropionic acid derivatives (Hutt & Caldwell, 1983), has been estimated to account for about 63% of the total metabolism of an orally administered dose of R(-)-ibuprofen (Lee et al, 1985) and as such assumes clinical importance.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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“…The issue with flurbiprofen and the other aryl propionic acids is complicated further by a metabolic inversion of the pharmacologically inactive R(-)-enantiomer to the active S(+)-enantiomer (Hutt & Caldwell, 1983;Caldwell et al, 1988a,b). This process is variable with respect to drug, species and between individuals.…”

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.

Young

Aarons

Toon

1991

Brit J Clinical Pharma

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“…The absolute configuration of this chiral centre has profound effects on the pharmacokinetics and pharmacodynamics of these compounds (Hutt and Caldwell 1984) with the pharmacological activity of these compounds, the inhibition of cyclooxygenase activity, being almost exclusively attributable to the (S)-enantiomer in vivo, the (R)-enantiomer being either only weakly active or completely inactive (Hutt and Caldwell 1983 ;Suesa et al 1993). Despite this, the majority of these compounds are administered as racemic mixtures because of their ease of synthesis in comparison with producing pure enantiomers.…”

Section: Introductionmentioning

confidence: 99%

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

Thomason

Rhys‐Williams

Lloyd

et al. 1998

Journal of Applied Microbiology

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The fungus Verticillium lecanii has previously been shown to be capable of inverting the chirality of ibuprofen and 2-phenylpropionic acid from the (R)-enantiomer to the corresponding (S)-antipode, a phenomenon also observed in mammalian systems including man. An investigation is reported here into the substrate specificity of the enzyme system present in V. lecanii using the following 2-arylpropionic acids : ibuprofen, ketoprofen, indoprofen, suprofen, flurbiprofen and fenoprofen, together with the structurally related compounds 2-phenylbutyric acid, 2-phenoxypropionic acid, mandelic acid, atrolactic acid, etodolac and amethoxyphenylpropionic acid. The results demonstrated that V. lecanii is capable of inverting the chirality of all the 2-arylpropionic acids investigated. All were inverted in the (R) to (S) direction with the exception of ketoprofen, where inversion was observed in the reverse direction. Using the structurally related compounds as substrates, the size of the alkyl substituent at the a-carbon at the methyl group, and the presence of the methyl group at the chiral centre, were found to be critical. These results suggest that V. lecanii could be used as a basis for the production of pure enantiomers of the 2-arylpropionic acids in commercial biotransformations.

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The metabolic chiral inversion of 2-arylpropionic acids—a novel route with pharmacological consequences

Cited by 391 publications

References 36 publications

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

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

The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

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