Simultaneous determination of MK-0767 and seven metabolites in rat urine using liquid chromatography/tandem mass spectrometry

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Abstract
MK‐0767, 5‐[2,4‐dioxothiazolidin‐5‐yl)methyl]‐2‐methoxy‐N‐[[(4‐trifluoromethyl)phenyl]methyl]benzamide (I, Table 1), is a dual peroxisome proliferator‐activated receptor (PPAR) α/γ agonist previously studied for the treatment of type 2 diabetes and dyslipidemia. To support further toxicological studies in one of the animal species used in chronic testing of I, a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantification of I and seven metabolites in rat urine was developed and validated. In this method, urine samples were diluted with acetonitrile/methanol (50:50, v/v) and injected directly onto the column of an LC system. Detection was achieved by MS/MS using a turbo ion spray probe monitoring precursor → product ion combinations in selected reaction monitoring (SRM) mode. The linear range for I and three metabolites was 0.8–800 ng/mL, and 8–8000 ng/mL for four other metabolites found to be present in urine at higher concentrations than I. Intra‐day and inter‐day variation using this method were ≤13.0%. The method exhibited good linearity, reproducibility, specificity and sufficient sensitivity when used for the analysis of rat urine samples. Concentrations of I and its major metabolites in rat urine were determined in samples collected between 0–24 h after dosing on the last day of administration of nine daily oral doses to three male (1000 mg/kg/day) and three female (300 mg/kg/day) Sprague‐Dawley rats. The urinary concentrations of I and its metabolites were similar in male and female rats. The average concentrations of I were 0.51 and 0.33 μg/mL in male and female rats, respectively. Concentrations of four of the seven metabolites quantified were 6‐ to 45‐fold higher than those of I. The most abundant metabolite, with concentrations of 24.2 and 13.3 μg/mL in male and female rat urine, respectively, was a methyl sulfoxide derivative formed by oxidative cleavage of the thiazolidinedione ring, followed by S‐methylation and oxidation of the sulfide intermediate. Copyright © 2004 John Wiley & Sons, Ltd. Table 1. Molecular weight (MW), SRM transitions and structures of MK‐0767 (I) and its metabolites

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