The thioester dalcetrapib is undergoing Phase III clinical evaluation for the prevention and regression of atherosclerosis and the prevention of cardiovascular events through targeting cholesteryl ester transfer protein and increasing high-density lipoprotein cholesterol levels. Dalcetrapib undergoes rapid hydrolysis to generate the pharmacologically active form (dalcetrapib-thiol), which undergoes extensive metabolism via glucuronic acid conjugation, methylation, and hydroxylation, predominately forming the pharmacologically inactive S-methyl (dalcetrapib-S-Me) and S-glucuronide (dalcetrapib-S-Glu) metabolites. The purpose of this study was to characterize the absorption and disposition of dalcetrapib-thiol and its primary metabolites in cynomolgus monkeys following first pass through the intestines and liver using an in vivo dual portal and peripheral vein cannulation. Results showed the high influence of glucuronidation of dalcetrapib-thiol on the first-pass effect. Following passage through the primate intestinal wall, area under the plasma concentration-time curve indicated a marked loss (by ~85%) of active compound and formation of dalcetrapib-S-Glu and dalcetrapib-S-Me. Based on time to maximum drug concentrations (T(max)) values in the portal vein, metabolism of dalcetrapib-thiol to dalcetrapib-S-Glu appears to occur almost instantly (median T(max) 6.0 and 5.5 h, respectively), whereas methylation to dalcetrapib-S-Me occurs much more slowly (median T(max), 24 h). A relatively modest impact on systemic exposure followed hepatic first pass, with a further decrease in dalcetrapib-thiol exposure of 58% (AUC), a 3-fold reduction in exposure levels of dalcetrapib-S-Me and near-complete decrease in exposure of dalcetrapib-S-Glu. Passage of drug-related material through the intestinal wall and the liver results in an overall decrease of exposure to dalcetrapib-thiol of >90%.