title: Human pharmacokinetics and interconversion of enantiomers of MK-0767, a dual PPARalpha/gamma agonist.
abstract: MK-0767, a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma 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).
authors.affiliation: Clinical Drug Metabolism, WP75B-100, PO Box 4, Merck Research Laboratories, West Point, PA 19486-0004, USA. ronda_rippley@merck.com
authors.forename: Ronda K
authors.initials: RK
authors.lastname: Rippley
authors.forename: Kerri X
authors.initials: KX
authors.lastname: Yan
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Matthews
authors.forename: Howard E
authors.initials: HE
authors.lastname: Greenberg
authors.forename: Gary A
authors.initials: GA
authors.lastname: Herman
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D019998:Racemases and Epimerases / Q000737:chemistry / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D013237:Stereoisomerism; D013607:Tablets; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C487303:MK0767; D047493:PPAR alpha; D047495:PPAR gamma; D012709:Serum Albumin; D013607:Tablets; D013844:Thiazoles; D003402:Creatine Kinase; D019998:Racemases and Epimerases