Pharmacokinetics, metabolism, and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in rats and rhesus monkeys.
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.
Tan
Eugene Y
EY
Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Hartmann
Georgy
G
Chen
Qing
Q
Pereira
Antonio
A
Bradley
Scott
S
Doss
George
G
Zhang
Andy Shiqiang
AS
Ho
Jonathan Z
JZ
Braun
Matthew P
MP
Dean
Dennis C
DC
Tang
Wei
W
Kumar
Sanjeev
S
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
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D020719:Glucuronides; D023303:Oxazolidinones; C530884:anacetrapib