title: Pharmacokinetics, metabolism, and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in rats and rhesus monkeys.
abstract: The pharmacokinetics and metabolism of anacetrapib (MK-0859), a novel cholesteryl ester transfer protein inhibitor, were examined in rats and rhesus monkeys. Anacetrapib exhibited a low clearance in both species and a moderate oral bioavailability of approximately 38% in rats and approximately 13% in monkeys. The area under the plasma concentration-time curve in both species increased in a less than dose-proportional manner over an oral dose range of 1 to 500 mg/kg. After oral administration of [(14)C]anacetrapib at 10 mg/kg, approximately 80 and 90% of the radioactive dose was recovered over 48 h postdose from rats and monkeys, respectively. The majority of the administered radioactive dose was excreted unchanged in feces in both species. Biliary excretion of radioactivity accounted for approximately 15% and urinary excretion for less than 2% of the dose. Thirteen metabolites, resulting from oxidative and secondary glucuronic acid conjugation, were identified in rat and monkey bile. The main metabolic pathways consisted of O-demethylation (M1) and hydroxylation on the biphenyl moiety (M2) and hydroxylation on the isopropyl side chain (M3); these hydroxylations were followed by O-glucuronidation of these metabolites. A glutathione adduct (M9), an olefin metabolite (M10), and a propionic acid metabolite (M11) also were identified. In addition to parent anacetrapib, M1, M2, and M3 metabolites were detected in rat but not in monkey plasma. Overall, it appears that anacetrapib exhibits a low-to-moderate degree of absorption after oral dosing and majority of the absorbed dose is eliminated via oxidation to a series of hydroxylated metabolites that undergo conjugation with glucuronic acid before excretion into bile.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Tan
authors.forename: Georgy
authors.initials: G
authors.lastname: Hartmann
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Antonio
authors.initials: A
authors.lastname: Pereira
authors.forename: Scott
authors.initials: S
authors.lastname: Bradley
authors.forename: George
authors.initials: G
authors.lastname: Doss
authors.forename: Andy Shiqiang
authors.initials: AS
authors.lastname: Zhang
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Ho
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Braun
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Dean
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D001774:Blood Chemical Analysis; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000032:analysis / Q000097:blood / Q000737:chemistry / Q000652:urine; D006900:Hydroxylation; D007408:Intestinal Absorption; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D023303:Oxazolidinones / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D014556:Urine / Q000737:chemistry
chemical_list: D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D020719:Glucuronides; D023303:Oxazolidinones; C530884:anacetrapib