Received for publication June 30, 2008.
Revised August 8, 2008.
Accepted for publication August 8, 2008.

Pharmacokinetics, Metabolism and Excretion of Torcetrapib, a CETP Inhibitor, in Humans

Abstract

The pharmacokinetics, metabolism and excretion of torcetrapib, a selective inhibitor of human cholesteryl ester transfer protein (CETP), was investigated in healthy human male volunteers following oral administration of [¹⁴C]torcetrapib (120 mg dose). The total mean recovery of radiolabeled dose after 21 days was 75.7% and most of the dose (63%) was excreted in the urine. The total circulating radioactivity and unchanged torcetrapib plasma concentrations increased over the first six hours then declined slowly with mean terminal elimination half-lives of 373 and 211 h. Metabolism of torcetrapib was extensive in humans. Only 5.2% of the total dose constituted unchanged torcetrapib in the feces while no parent was excreted unchanged in the urine. Similarly, pharmacokinetic analysis of total radioactivity and unchanged torcetrapib revealed that the AUC_0- of torcetrapib accounted for ~7.0% of the circulating radioactivity. Torcetrapib was metabolized to numerous metabolites via oxidation. The primary metabolic pathway involved initial oxidative decarbamoylation followed by extensive further oxidation resulting in the formation of bistrifluoromethylbenzoic acid (M1) and quinaldic acid (M4) metabolites. A mean 40% of the total dose was excreted in the urine as M4 (and its glucuronide and urea conjugates) whereas 7.0% of the total dose was excreted as M1. In vitro studies using human subcellular fractions suggested that initial metabolism of torcetrapib proceeds via CYP3A-mediated decarbamoylation. Subsequent oxidations lead to the major circulating and excretory metabolites M1 and M4.

Key words: excretion, mass spectrometry