The Contribution of Enantiomers to Variability in Response to Anti-Inflammatory Drugs

Km, Williams; Day, RO

doi:10.1007/978-3-0348-9160-8_7

Cited by 10 publications

(3 citation statements)

References 17 publications

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“…Inhibition of prostaglandin synthesis is a direct cause of topical irritation of the gastric mucosa. Williams and Day (1988) suggested using the R( -)-enantiomen as prodrugs for the NSAIDs which are inverted at a significant rate, in order to reduce these toxic effects.…”

Section: Resultsmentioning

confidence: 99%

Pharmacological aspects of chiral nonsteroidal anti‐inflammatory drugs

Muller

Payan

Lapicque

et al. 1990

Fundamemntal Clinical Pharma

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Most NSAIDs are chiral molecules: they exist under 2 configurations of non-superimposable mirror images which are termed enantiomers or optical isomers or optical antipodes. Direct or indirect (resolution) methods are used to separate this equal mixture of compounds. Some of the enantiomers of the NSAIDs are able to undergo chiral inversion from the inactive R(-) to the active S(+) form. The pharmacokinetics in terms of absorption, distribution, metabolism, protein binding and elimination may be different for the 2 enantiomers, leading to interindividual variability in clinical response and drug toxicity.

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Section: Resultsmentioning

confidence: 99%

Pharmacological aspects of chiral nonsteroidal anti‐inflammatory drugs

Muller

Payan

Lapicque

et al. 1990

Fundamemntal Clinical Pharma

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“…Most of these chiral NSAlDs are administered in their racemic form, except for naproxen. The pharmacological activity of the 2 enantiomers differs, since in vitro studies have shown that the anti-inflammatory effect seems to result mainly from the S( +) form (Caldwell et al 1988;Williams & Day 1988). The R( -) enantiomer can, however, have analgesic effects, as demonstrated with flurbiprofen (Brune et al 1991).…”

mentioning

confidence: 97%

Protein Binding and Stereoselectivity of Nonsteroidal Anti-Inflammatory Drugs

Lapicque¹,

Muller²,

Payan³

et al. 1993

Clinical Pharmacokinetics

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Stereoselective binding of nonsteroidal anti-inflammatory drugs (NSAIDs) can be studied using various techniques. Thus the results obtained by different investigators may be poorly consistent and even contradictory. NSAIDs are bound stereoselectively to serum albumin to different degrees depending on the drug investigated (ibuprofen, indoprofen, carprofen, etodolac, ketoprofen and flurbiprofen). For other drugs, both enantiomers are bound to a similar extent (pirprofen, fenoprofen). This stereoselectivity could vary with experimental conditions, in particular with protein concentration (ketoprofen, etodolac), leading to individual differences. Finally, the stereoselectivity of protein binding and of pharmacokinetics can be compared: differences in binding between enantiomers can explain their differences in pharmacokinetics, once metabolic properties such as inversion have been taken into account.

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“…Novel metabolic pathways, such as the chiral inversion of R-2-arylpropionates Caldwell et al 1988;Williams & Day 1988) and the enantioselective uptake of the R-enantiomers into lipids (Fears 1985;Williams et al 1986;Sallustio et al 1988) have become evident by a study of the disposition of the enantiomers of these drugs. Both pathways are dependent on the enantioselective formation of CoA thioesters, a finding which has afforded another interesting insight into drug disposition (Nakamura et af.…”

Section: Metabolismmentioning

confidence: 99%

Chirality: Pharmacokinetics and Pharmacodynamics in 3 Dimensions

Williams

1989

Clin Exp Pharma Physio

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1. Biological macromolecules are able to distinguish between enantiomeric substrates. A three-point interaction between the drug enantiomers and the macromolecule (Easson-Stedman hypothesis) can frequently account for this selectivity. 2. Significant pharmacodynamic differences between enantiomers are more the rule than the exception. 3. Pharmacokinetic differences between enantiomers are, in general, not as great as the pharmacodynamic differences. However, stereoselective protein binding, metabolism and renal clearance are still very important aspects of understanding drug disposition and the time course of drug action. 4. There may be pharmacokinetic and pharmacodynamic enantiomer-enantiomer interactions. Consequently, the activity and disposition of a racemic drug may not be the simple sum of the activities and disposition of the individual enantiomers. 5. Enantiomers have been used as sensitive 3-dimensional probes to establish structure-activity relationships, to provide insights into genetic polymorphism of drug metabolism, and to provide insights into other aspects of drug disposition. 6. A need for a 3-dimensional understanding of pharmacodynamics and pharmacokinetics is implicit in the asymmetric nature of biological environments.

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The Contribution of Enantiomers to Variability in Response to Anti-Inflammatory Drugs

Cited by 10 publications

References 17 publications

Pharmacological aspects of chiral nonsteroidal anti‐inflammatory drugs

Pharmacological aspects of chiral nonsteroidal anti‐inflammatory drugs

Protein Binding and Stereoselectivity of Nonsteroidal Anti-Inflammatory Drugs

Chirality: Pharmacokinetics and Pharmacodynamics in 3 Dimensions

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