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Human Pharmacokinetics and Interconversion of Enantiomers of MK‐0767, a Dual PPARα/γ Agonist
Author(s) -
Rippley Ronda K.,
Yan Kerri X.,
Matthews Natalie D.,
Greenberg Howard E.,
Herman Gary A.,
Wagner John A.
Publication year - 2007
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270006297141
Subject(s) - pharmacokinetics , enantiomer , chemistry , agonist , partial agonist , in vivo , pharmacology , dyslipidemia , ppar agonist , receptor , stereochemistry , endocrinology , diabetes mellitus , biochemistry , medicine , biology , microbiology and biotechnology
MK‐0767, a dual peroxisome proliferator‐activated receptor (PPAR) α/γ agonist, has been studied as a potential treatment of type 2 diabetes and dyslipidemia. The pharmacokinetics and interconversion of (+)‐(R)‐MK‐0767 and (−)‐(S)‐MK‐0767 were evaluated following oral administration of each single enantiomer and the racemate to healthy subjects. The results demonstrate that, consistent with in vitro experiments, chiral inversion occurs rapidly in vivo, and interconversion equilibrium favors (+)‐(R). After all treatments, a stable ratio (R/S) of 2 to 2.5 was achieved within 8 hours in most individuals, congruent with model‐based estimates of interconversion half‐life. In addition, the pharmacokinetics of each enantiomer were generally similar regardless of treatment. Modeling and simulation of enantiomer disposition suggest that the observed predominance of (+)‐(R)‐MK‐0767 in plasma may result from differential volumes of distribution between (−)‐(S) and (+)‐(R), preferential conversion from (−)‐(S) to (+)‐(R), or a combination of these, but not faster clearance of (−)‐(S) compared to (+)‐(R).