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Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats

, : Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats. Drug Metabolism and Disposition: the Biological Fate of Chemicals (): -

NlmCategory="UNASSIGNED">2-Arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drugs are commonly used in racemic mixtures (rac) for clinical use. 2-APA undergo unidirectional chiral inversion of the in vivo inactive R-enantiomer to the active S-enantiomer. Inflammation causes the reduction of metabolic activities of drug-metabolizing enzymes such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase. However, it is unclear whether inflammation affects the stereoselective pharmacokinetics and chiral inversion of 2-APA such as ibuprofen (IB). We examined the effects of inflammation on the pharmacokinetics of R-IB and S-IB after intravenous (i.v.) administration of rac-IB, R-IB, and S-IB to adjuvant-induced arthritic (AA) rats, an animal model of inflammation. The plasma protein binding of rac-IB, glucuronidation activities for R-IB and S-IB, and CYP contents of liver microsomes in AA rats were determined. Total clearance (CLtot) of IB significantly increased in AA rats although the glucuronidation activities for IB, and CYP contents of liver microsomes decreased in AA rats. We presumed that the increased CLtot of IB in AA rats was caused by the elevated plasma unbound fraction of IB due to decreased plasma albumin levels in AA rats. Notably, CLtot of R-IB but not S-IB significantly increased in AA rats after i.v. administration of rac-IB. These results suggested that AA could affect drug efficacies following stereoselective changes in the pharmacokinetics of R-IB and S-IB.


PMID: 27927688

DOI: 10.1124/dmd.116.073239

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