Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Tan, Eugene; Hartmann, Georgy; Chen, Qing; Pereira, Aline Pinto; Bradley, Scott A.; Doss, George A.; Zhang, Andy Shiqiang; Ho, Joanne; Braun, Matthew P.; Dean, Dennis C.; Tang, Wei; Kumar, Sanjeev

doi:10.1124/dmd.109.028696

Cited by 31 publications

(37 citation statements)

References 23 publications

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“…These results are consistent with data from preclinical toxicology species, in which anacetrapib was eliminated mainly in feces also (Tan et al, 2010). Although the absolute oral bioavailability of anacetrapib is not known, the bioavailability (and oral absorption) of anacetrapib in the preclinical safety species (rats and monkeys) ranged from 13 to 38% at oral doses of 1 to 5 mg/kg (Tan et al, 2010). Hence, it can be concluded that anacetrapib probably has low-to-moderate oral bioavailability/absorption in humans and a significant portion of the radioactivity in feces can be attributed to nonabsorbed anacetrapib.…”

Section: Discussionsupporting

confidence: 92%

“…Anacetrapib was eliminated primarily via the fecal route (87% of dose), and urinary elimination accounted for only ϳ0.1% of the dose. These results are consistent with data from preclinical toxicology species, in which anacetrapib was eliminated mainly in feces also (Tan et al, 2010). Although the absolute oral bioavailability of anacetrapib is not known, the bioavailability (and oral absorption) of anacetrapib in the preclinical safety species (rats and monkeys) ranged from 13 to 38% at oral doses of 1 to 5 mg/kg (Tan et al, 2010).…”

Section: Discussionsupporting

confidence: 88%

“…The metabolite identification was performed by comparison of the LC retention times and CID spectra (both nominal mass and high resolution) of metabolites in biological samples with those of the available synthetic standards of M1, M2, and M3. The nominal mass spectral data for these metabolites were discussed in the companion article on the metabolism of anacetrapib in rats and monkeys (Tan et al, 2010), and only high-resolution mass spectral data are presented in this manuscript. Figures 3 to 6 depict the high-resolution CID fragmentation spectra for anacetrapib and M1, M2, and M3 metabolites, along with the proposed structures of various fragment ions and their theoretical accurate masses.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, it has been demonstrated previously that within the relevant dose range, anacetrapib is capable of effectively decreasing plasma LDL (ϳ40%) and raising HDL (ϳ130%) levels (Krishna et al, 2007). Because anancetrapib has a high affinity for plasma CETP (Tan et al, 2010), this protein, possibly along with others in plasma, contributes to its high observed plasma protein binding (Ͼ99.5%).…”

Section: Discussionmentioning

confidence: 97%

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Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Kumar¹,

Tan²,

Hartmann³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an openlabel study in which six healthy male subjects received a single oral dose of 150 mg and 165 Ci of [ 14 C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (ϳ2 M equivalents of [ 14 C]anacetrapib) was achieved ϳ4 h postdose. The parent compound was the major radioactive component (79-94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing <14% of the radioactivity in plasma or fecal samples. In vitro data indicated that anacetrapib is metabolized mainly by CYP3A4 to form M1, M2, and M3. Overall, these data, along with those from other preclinical and clinical studies, indicate that anacetrapib probably exhibits a low-to-moderate degree of oral absorption in humans and the absorbed fraction of the dose is eliminated largely via CYP3A4-catalyzed oxidative metabolism, followed by excretion of metabolites by the biliary-fecal route.As described in the companion article, anacetrapib (MK-0859, [4S,5R]-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4Ј-fluoro-2Ј-methoxy-5Ј-(propan-2-yl)-4-(trifluoromethyl)[1,1Ј-biphenyl]-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one; Merck, Whitehouse Station, NJ) is a potent and selective inhibitor of CETP and is undergoing development as an oral drug for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. In phase I and II clinical trials, anacetrapib has shown impressive effects on the plasma lipid profile including increases in HDL cholesterol levels of ϳ130% and reduction in LDL cholesterol levels by ϳ40%, with no associated major adverse events (Krishna et al., 2007(Krishna et al., , 2008Bloomfield et al., 2009). Furthermore, as opposed to torcetrapib (Pfizer Inc., New York, NY), anacetrapib showed no treatment-related effect on blood pressure in a 24-h ambulatory blood pressure clinical trial (Krishna et al., 2007). These preliminary pharmacodynamic and safety observations with anacetrapib provide support for further evaluation of the efficacy of this drug in cardiovascular disease upon long-term treatment.The objective of this study was to investigate the routes of elimination and the excretion mass balance after a single oral dose of [ 14 C]anacetrapib in humans. Major metabolites of anacetrapib were identified in humans and compared with those de...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

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Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Kumar¹,

Tan²,

Hartmann³

et al. 2009

Drug Metab Dispos

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“…Whereas preclinical studies in rats and monkeys have shown that anacetrapib is characterized by low clearance, a high degree of protein binding, and a high volume of distribution (Tan et al, 2010), the data from these single-dose pharmacokinetic studies were unable to predict the tissue accumulation properties and the long t ½ observed in this study. In a previous mouse pharmacokinetic study where anacetrapib was given i.v.…”

Section: Discussionmentioning

confidence: 64%

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Hartmann

Kumar

Johns

et al. 2015

Drug Metabolism and Disposition

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The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibits a long terminal half-life (t ½ ) in humans; however, the dispositional mechanisms that lead to this long t ½ are still being elucidated. As it is hypothesized that disposition into adipose tissue and binding to CETP might play a role, we sought to delineate the relative importance of these factors using a preclinical animal model. A multiple-dose pharmacokinetic study was conducted in C57BL6 wild-type (WT) lean, WT diet-induced obese (DIO), natural flanking region (NFR) CETP-transgenic lean, and NFR-DIO mice. Mice were dosed orally with 10 mg/kg anacetrapib daily for 42 days. Drug concentrations in blood, brown and white adipose tissue, liver, and brain were measured up to 35 weeks postdose. During dosing, a 3-to 9-fold accumulation in 72-hour postdose blood concentrations of anacetrapib was observed. Drug concentrations in white adipose tissue accumulated ∼20-to 40-fold, whereas 10-to 17-fold accumulation occurred in brown adipose and approximately 4-fold in liver. Brain levels were very low (<0.1 mM), and a trend of accumulation was not seen. The presence of CETP as well as adiposity seems to play a role in determining the blood concentrations of anacetrapib. The highest blood concentrations were observed in NFR DIO mice, whereas the lowest concentrations were seen in WT lean mice. In adipose and liver tissue, higher concentrations were seen in DIO mice, irrespective of the presence of CETP. This finding suggests that white adipose tissue serves as a potential depot and that disposition into adipose tissue governs the long-term kinetics of anacetrapib in vivo.

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Torcetrapib and Dalcetrapib Safety: Relevance of Preclinical In Vitro and In Vivo Models

Niesor

Greiter‐Wilke

Müller

2015

Methods and Principles in Medicinal Chemistry

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Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Cited by 31 publications

References 23 publications

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Torcetrapib and Dalcetrapib Safety: Relevance of Preclinical In Vitro and In Vivo Models

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