title: Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats.
abstract: 2-Arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drugs are commonly used in racemic mixtures (rac) for clinical use. 2-APA undergoes unidirectional chiral inversion of the in vivo inactiveR-enantiomer to the activeS-enantiomer. Inflammation causes the reduction of metabolic activities of drug-metabolizing enzymes such as cytochrome P450 (P450) 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 ofR-IB andS-IB after intravenous administration ofrac-IB,R-IB, andS-IB to adjuvant-induced arthritic (AA) rats, an animal model of inflammation. The plasma protein binding ofrac-IB, glucuronidation activities forR-IB andS-IB, and P450 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 P450 contents of liver microsomes decreased in AA rats. We presumed that the increased CLtotof IB in AA rats was caused by the elevated plasma unbound fraction of IB due to decreased plasma albumin levels in AA rats. Notably, CLtotofR-IB but notS-IB significantly increased in AA rats after intravenous administration ofrac-IB. These results suggested that AA could affect drug efficacies after stereoselective changes in the pharmacokinetics ofR-IB andS-IB.
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Kindai University, Higashi-osaka, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ikuta
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Kindai University, Higashi-osaka, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawase
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Kindai University, Higashi-osaka, Osaka, Japan iwaki@phar.kindai.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwaki
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001169:Arthritis, Experimental / Q000097:blood / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D007052:Ibuprofen / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D020719:Glucuronides; D003577:Cytochrome P-450 Enzyme System; D007052:Ibuprofen