Dalcetrapib
Liver tumors seen in a 2-year mouse study of dalcetrapib trace to a rodent-specific pathway not relevant to humans (Toxicol Appl Pharmacol 2012)
Original title: Monitoring Cyp2b10 mRNA expression at cessation of 2-year carcinogenesis bioassay in mouse liver provides evidence for a carcinogenic mechanism devoid of human relevance: the dalcetrapib experience
In a 2-year mouse carcinogenesis bioassay of dalcetrapib required for regulatory review, male mice showed increased liver weight and statistically increased hepatocellular adenoma and carcinoma. Since induction of hepatic Cyp2b10 mRNA and enzyme activity signals activation of the nuclear receptor CAR, a well-established driver of rodent-specific liver tumors, researchers monitored Cyp2b10 in liver samples from roughly a third of male mice per dose group. Cyp2b10 mRNA was strongly induced by dalcetrapib, with group-average fold-induction rising from 48-fold at 250 mg per kg per day to 160-fold at 750 mg per kg per day, alongside an approximate doubling of total Cyp P450 content and a 9-fold increase in Cyp2b10-selective enzyme activity. The data strongly implicate CAR activation, a mechanism without relevance to human hepatocarcinogenesis.
Original abstract
Introduction: Dalcetrapib is a cholesteryl ester transfer protein (CETP) modulator in clinical assessment for cardiovascular outcome benefits. In compliance with regulatory requirements, dalcetrapib was evaluated in rodent 2-year carcinogenesis bioassays. In the mouse bioassay, male mice demonstrated increased liver weight and statistically increased incidences of hepatocellular adenoma/carcinoma. Hepatic cytochrome p450 (Cyp) 2b10 mRNA induction and increased Cyp2b10 enzyme activity signify activation of hepatic nuclear receptor constitutive androstane receptor (CAR), a widely established promoter of rodent-specific hepatic tumors. We therefore monitored hepatic Cyp2b10 mRNA and its enzyme activity in a subset of dalcetrapib-treated male mice from the bioassay.
Methods: Liver samples were obtained from ~1/3 of male mice from each dose group including vehicle-controls (mean and earliest study day of death 678 and 459 respectively). Quantitative real time PCR (qRT-PCR) was performed to determine Cyp2b10 mRNA expression and Cyp1a-, Cyp2b10- and Cyp3a-selective activities were monitored.
Results: Cyp2b10 mRNA was strongly induced by dalcetrapib with an expected wide inter-individual variation (5-1421-fold). Group average fold-induction versus vehicle-controls showed a dose-related increase from 48-fold (250mg/kg/day) to 160-fold (750mg/kg/day), which declined slightly at 2000mg/kg/day (97-fold). Cyp enzyme activities showed approximate doubling of total Cyp P450 content per milligram protein and a 9-fold increase in Cyp2b10-selective pentoxyresorufin O-dealkylase activity (750mg/kg/day).
Discussion: These data from hepatic Cyp2b10 monitoring are strongly suggestive of CAR activation by dalcetrapib, a mechanism devoid of relevance towards hepatocarcinogenesis in humans; results show feasibility of Cyp2b10 as a surrogate marker for this mechanism at cessation of a carcinogenesis bioassay.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.