IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)-PHENYL] METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. II. IDENTIFICATION OF METABOLITES BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

• Published in: Drug metabolism and disposition Vol. 32; no. 9; p. 1023
• Main Authors: David Q. Liu, Bindhu V. Karanam, George A. Doss, Rick R. Sidler, Stella H. Vincent, Cornelis E.C.A. Hop
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01-09-2004
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.104.000059

The in vitro metabolism of MK-0767 [(±)-5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy- N -[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a novel 2,4-thiazolidinedione (TZD)-containing peroxisome proliferator-activated
receptor α/γ agonist, was studied in rat, dog, monkey, and human liver microsomes and hepatocytes, as well as in recombinant
human CYP3A4-containing microsomes. Twenty-two metabolites (some at trace levels) were detected by liquid chromatography-tandem
mass spectrometry analysis. All appeared to be phase I metabolites except for a glucuronide conjugate of a hydroxylated metabolite
that was detected at trace levels. A constant neutral loss scan experiment performed on a triple quadrupole mass spectrometer
proved to be very useful for resolving the metabolites from endogenous compounds. It was observed that the initial site of
metabolism of MK-0767 was at the TZD ring leading to two major metabolites, namely the 5-hydroxy-TZD metabolite (M24) and
the mercapto metabolite (M22). The latter was formed via the cleavage of the TZD ring with the elimination of the carbonyl
adjacent to the sulfur atom. The structure of M24 was established by accurate mass measurements and NMR analysis. This hydroxy-TZD
metabolite might represent an important precursor for a group of metabolites formed by TZD ring opening and subsequent loss
of the sulfur moiety. The mercapto metabolite, on the other hand, is probably the key precursor for the TZD ring-opened metabolites
with retention of the sulfur, even though the detailed mechanism of the ring scission remains to be characterized. From these
studies, it was concluded that the TZD ring was the major site of metabolism of MK-0767. All the metabolites produced in vitro
from human preparations were detected in the corresponding preparations from the nonclinical species.