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Enantiomer ratio of MK‐0767 in humans and nonclinical species
Author(s) -
Shen Zhongzhou,
Bakhtiar Ray,
Komuro Masakatsu,
Awano Katsuya,
Taga Fukutaro,
Colletti Adria,
Hora Don,
Feeney William,
Iliff Susan,
Franklin Ronald B.,
Vincent Stella
Publication year - 2005
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.1897
Subject(s) - in vivo , chemistry , in vitro , enantiomer , pharmacology , agonist , stereochemistry , receptor , biochemistry , medicine , microbiology and biotechnology , biology
MK‐0767, (±)‐5‐[(2,4‐dioxothiazolidin‐5‐yl)methyl]‐2‐methoxy‐ N ‐[[(4‐trifluoromethyl)phenyl]methyl]benzamide, is a thiazolidinedione‐containing dual peroxisome proliferator‐activated receptor (PPAR) α / γ agonist that has been studied as a potential treatment for patients with type 2 diabetes. MK‐0767 contains a chiral center at the C‐5 position of the thiazolidinedione ring and was being developed as the racemate, due to the rapid interconversion of its enantiomers in biological samples. In the present work the in vitro and in vivo concentration ratios of the (+)‐(R) to (−)‐(S) enantiomers of MK‐0767 were determined in plasma from humans ( in vitro only) and nonclinical species used in the toxicological evaluation of rac ‐MK‐0767, namely CD‐1 mice, Sprague‐Dawley rats, beagle dogs, New Zealand white rabbits, and rhesus monkeys. The R/S ratio was determined by chiral liquid chromatography/tandem mass spectrometry. Species differences were observed in the in vitro and in vivo enantiomeric ratios, as well as differences between in vitro and in vivo in some species. The in vitro R/S ratio was similar in dogs and humans (∼1.5–1.7). In rats and monkeys, the ratio was approximately unity, both in vitro and in vivo . In mice, the ratio was higher in vitro (∼1) than in vivo (∼0.6), while in rabbits it was higher in vivo (∼1) than in vitro (∼0.5). These results suggested that differential binding of the MK‐0767 enantiomers to plasma and tissue proteins and other macromolecules may be affecting the R/S ratio both in vitro and in vivo , since in protein‐free systems MK‐0767 exists as the racemate. Copyright © 2005 John Wiley & Sons, Ltd.