RT Journal Article
SR Electronic
T1 Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 459
OP 473
DO 10.1124/dmd.109.028696
VO 38
IS 3
A1 Eugene Y. Tan
A1 Georgy Hartmann
A1 Qing Chen
A1 Antonio Pereira
A1 Scott Bradley
A1 George Doss
A1 Andy Shiqiang Zhang
A1 Jonathan Z. Ho
A1 Matthew P. Braun
A1 Dennis C. Dean
A1 Wei Tang
A1 Sanjeev Kumar
YR 2010
UL http://dmd.aspetjournals.org/content/38/3/459.abstract
AB 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 ∼38% in rats and ∼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 [14C]anacetrapib at 10 mg/kg, ∼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 ∼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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics