Metabolism, pharmacokinetics, and excretion of a cholesteryl ester transfer protein inhibitor, torcetrapib, in rats, monkeys, and mice: characterization of unusual and novel metabolites by high-resolution liquid chromatography-tandem mass spectrometry and 1H nuclear magnetic resonance.
The disposition of torcetrapib {(-)-[2R,4S] 4-[(3,5-bis-trifluoromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester}, a cholesteryl ester transfer protein inhibitor, was studied in rats, monkeys, and mice after oral administration of a single dose of [14C]torcetrapib. Total mean recoveries of the radiocarbon were 90.9, 93.4, and 86.8% from mice, rats, and monkeys, respectively. Excretion of radioactivity was rapid and nearly complete within 48 h after dosing, with a majority excreted in the feces in all species. Torcetrapib was not detected in the urine and/or bile across species, suggesting that it is primarily cleared by metabolism in these species. More than 28 metabolites were identified in all species and were products of oxidation and conjugation pathways. The primary metabolic pathways of torcetrapib involved hydrolysis of the carbamate ester (M2) and the oxidation of the ethyl moieties. M2 was subsequently metabolized in parallel by oxidative cleavage to novel and unusual quinoline metabolites (M3, M4, M5, M9, and M17), M1 (bis trifluoromethyl benzoic acid), and M28 [3,5-bis(trifluoromethyl)phenyl-(methoxycarbonyl)methanesulfonic acid]. The structures of several metabolites were established by high-resolution liquid chromatography-tandem mass spectrometry and 1H NMR. The major circulating and excretory metabolites in mice, rats and monkeys were species-dependent; however, several common metabolites were observed in more than one species. In addition to parent torcetrapib, M1, M3, and M4 in rats, M4 and M17 in mice, and M3 and M8 in monkeys were detected as the major circulating metabolites. A mechanism for the formation of an unusual metabolite M28 has been proposed.
Prakash
Chandra
C
Department of Pharmacokinetics, Pfizer Global Research and Development, Groton, Connecticut, USA. chandra.prakash@biogenidec.com
Chen
Weichao
W
Rossulek
Michelle
M
Johnson
Kim
K
Zhang
Chenghong
C
O'Connell
Thomas
T
Potchoiba
Michael
M
Dalvie
Deepak
D
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D051379:Mice; D011804:Quinolines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D011804:Quinolines; C483909:torcetrapib