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Drug Metabolism and Disposition Fast Forward
First published on June 30, 2004; DOI: 10.1124/dmd.104.000224

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Received for publication April 13, 2004.
Revised June 23, 2004.
Accepted for publication June 24, 2004.

Species Differential Stereoselective Oxidation of a Methylsulfide of MK-0767, a PPAR Dual Agonist

BINDHU V KARANAM 1*, Christopher J Welch 2, Vijay G Reddy 2, Jennifer Chilenski 2, Mirlinda Biba 2, Stella H Vincent 3

1 MERCK RESEARCH LABORATORIES 2 Merck Research Laboratories, Rahway, NJ 3 Merck Research Laboratories

* Address correspondence to: E-mail: bindhu_karanam{at}merck.com

Abstract

MK-0767, (±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-trifluoromethyl) phenyl]methy]benzamide, a thiazolidinedione (TZD)-containing PPAR agonist,is a rapidly interconverting racemate that possesses a chiral center at the 5-position of the TZD ring. M25 is a methyl sulfide metabolite generated from MK-0767 following CYP3A4-mediated TZD ring opening and subsequent methylation of the sulfide intermediate, M22. M25, a major in vitro and in vivo metabolite, was further metabolized in liver microsomes to the methyl sulfoxide, M16, with two chiral centers, and the methyl sulfone, M20, with one chiral center. Previous studies demonstrated that both CYP3A4 and flavin monooxygenase-3 (FMO3) catalyzed the formation of M16, while M20 was formed exclusively by CYP3A4. The relative contribution of CYP3A4 and FMO3 in the formation of M16 in human and preclinical species was evaluated by chiral analysis using supercritical fluid chromatography. No stereoselectivity was observed in incubations of M25 with human and rhesus liver and recombinant CYP3A4 microsomes, whereas a high degree of stereoselectivity (63 to >99% enantiomeric excess) was observed in rat and dog liver and human recombinant FMO3 microsomes. Also, polyclonal anti-rat CYP3A2 antibody and CYP chemical inhibitors did not inhibit the oxidation of M25 in rat liver microsomes. Furthermore, M25 oxidation was more sensitive to heat inactivation at pH 8 and 8.7 in rat and dog liver microsomes than in human and monkey liver microsomes, consistent with the involvement of FMOs. Collectively, these results indicated that S-oxidation of M25 was catalyzed primarily by CYP enzymes in human and monkey liver microsomes, and by FMO enzymes in rat and dog liver microsomes.


Key words: cytochrome P450 catalyzed oxidations, flavin-containing monooxygenase, human CYP enzymes, microsomes


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