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) alpha/gamma 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 < or = 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 microg/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 microg/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.
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Authors | Zhongzhou Shen, Christopher Kochansky, Ray Bakhtiar, Ronald B Franklin, Stella H Vincent |
Journal | Rapid communications in mass spectrometry : RCM
(Rapid Commun Mass Spectrom)
Vol. 18
Issue 18
Pg. 2113-20
( 2004)
ISSN: 0951-4198 [Print] England |
PMID | 15317046
(Publication Type: Comparative Study, Evaluation Study, Journal Article, Validation Study)
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Copyright | Copyright 2004 John Wiley & Sons, Ltd. |
Chemical References |
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Topics |
- Administration, Oral
- Algorithms
- Animals
- Chromatography, Liquid
(methods)
- Dose-Response Relationship, Drug
- Male
- Mass Spectrometry
(methods)
- Rats
- Rats, Sprague-Dawley
- Sensitivity and Specificity
- Sex Factors
- Spectrometry, Mass, Electrospray Ionization
(methods)
- Thiazoles
(administration & dosage, pharmacokinetics, urine)
- Urinalysis
(methods)
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