Pharmacokinetics, Metabolism, and Excretion of Torcetrapib, a Cholesteryl Ester Transfer Protein Inhibitor, in Humans

Abstract

ABSTRACT:The pharmacokinetics, metabolism, and excretion of torcetrapib, a selective inhibitor of human cholesteryl ester transfer protein, were investigated in healthy human male volunteers after oral administration of [ 14 C]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 6 h and 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, whereas no parent was excreted unchanged in the urine. Similarly, pharmacokinetic analysis of total radioactivity and unchanged torcetrapib revealed that the area under the concentration versus time curve from zero to infinity of torcetrapib accounted for ϳ7.0% 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 the initial metabolism of torcetrapib proceeds via CYP3A-mediated decarbamoylation. Subsequent oxidations lead to the major circulating and excretory metabolites M1 and M4.Torcetrapib {(Ϫ)-[2R,4S] 4-[(3,5-bis-trifluoromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester} was being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. It was withdrawn from development in 2006 when phase III studies showed excessive mortality in the treatment group receiving a combination of atorvastatin and the study drug (Howes and Kostner, 2007). Torcetrapib acts by inhibiting human cholesteryl ester transfer protein, which normally transfers cholesterol from highdensity lipoprotein (HDL) cholesterol to very-low-density lipoprotein or low-density lipoprotein (LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol) (Clark et al., 2006). Administration of torcetrapib alone or in combination with atorvastatin led to an increase in HDL and a decrease in LDL concentrations (Brousseau et al., 2004;Clark et al., 2004;McKenney et al., 2006).The pharmacokinetics of torcetrapib has been evaluated in the rat and monkey. The results from these studies have indicated that the drug was moderately absorbed with a bioavailability of 33 to 45% and readily distributed throughout the body (volume of distribution is 1.1-2.5 l/kg). The clearance of torcetrapib i...

Metabolism and Disposition of Oral Dabrafenib in Cancer Patients: Proposed Participation of Aryl Nitrogen in Carbon-Carbon Bond Cleavage via Decarboxylation following Enzymatic Oxidation

“…Carbon-carbon bond cleavage of an aryl-alkyl side chain was also described for torcetrapib in preclinical species, in which an aryl-ethyl to arylmethyl conversion occurred from an intermediate metabolite containing a quinoline ring (Dalvie et al, 2008). The authors proposed a mechanism of oxidation of the terminal carbon of the ethyl group to a carboxylic acid intermediate with subsequent decarboxylation.…”

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

“…First, we previously demonstrated that adipocytes have a functional renin angiotensin aldosterone system and produce aldosterone in a highly regulated manner (Briones et al, 2011(Briones et al, , 2012. Second, CETP inhibitors are lipid soluble and accumulate, to variable degrees, in adipocytes (Dalvie et al, 2008;Gotto et al, 2014). Third, by computational analysis, these drugs were found to bind to several endogenous proteins related to adipogenesis, such as PPARa, PPARb, PPARg, and LXR (Xie et al, 2009).…”

“…Considering the fact that CETP inhibitors are lipophilic and may accumulate in adipose tissue (Dalvie et al, 2008;Gotto et al, 2014), we hypothesized that adipocytes may be an extra-adrenal source of CETP inhibitor-induced aldosterone production.…”

Off-Target Vascular Effects of Cholesteryl Ester Transfer Protein Inhibitors Involve Redox-Sensitive and Signal Transducer and Activator of Transcription 3-Dependent Pathways

“…The CETP inhibitor concentrations used in this study were based on our previous findings (Rios et al, 2015) and on dose-response experiments where we evaluated the effect of the drugs on superoxide anion (O 2 2 ) production in VSMC from WKY (Supplemental Figure 1). The concentration used in our study is similar to or lower than the C max in humans treated with torcetrapib, dalcetrapib, or anacetrapib (Dalvie et al, 2008;Krishna et al, 2009;Derks et al, 2010), which may have (patho)physiologic significance.…”