TY - JOUR T1 - In Vitro and In vivo Metabolism and Pharmacokinetics of BMS-562086, a Potent and Orally Bioavailable Corticotropin Releasing Factor-1 (CRF<sub>1</sub>) Receptor Antagonist JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.043596 SP - dmd.111.043596 AU - Lian Zhou AU - Randy C. Dockens AU - Peggy Liu-Kreyche AU - Scott Grossman AU - Ramaswamy Iyer Y1 - 2012/01/01 UR - http://dmd.aspetjournals.org/content/early/2012/03/01/dmd.111.043596.abstract N2 - The absorption, distribution, metabolism and excretion (ADME), and the pharmacokinetic characteristics of BMS-562086 (pexacerfont; DPC-A69448) were investigated in vitro and in animals to support its clinical development. BMS-562086 was orally bioavailable in rats, dogs and chimpazees, with an absolute oral bioavailability of 40.1%, 58.8% and 58.5%, respectively. BMS-562086 was extensively metabolized in hepatocytes from all species and completely metabolized in rats. The primary biotransformation pathways found for BMS-562086 in both liver microsomal and hepatocyte preparations and in rats were similar. These included O-demethylation, hydroxylation at the N-alkyl side chain and N-dealkylation. Multiple CYP P450s including CYP3A4/5 were involved in the metabolic clearance of BMS-562086. Both renal and biliary excretion played a significant role in elimination of the metabolites of BMS-562086. The involvement of other metabolic enzymes in addition to CYP3A4/5 in elimination of BMS-562086 suggests a reduced potential for drug-drug interaction through modulation of CYP3A4/5. Chimpanzees proved to be a good animal model in predicting BMS-562086 human clearance. Virtual clinical trials performed with the SimCYP population-based ADME simulator suggested that a minimum dose of 100 mg daily would provide sufficient drug exposure to achieve plasma concentrations above the projected human efficacious plasma concentration of BMS-562086 (&gt;500 nM). In summary, BMS-562086 exhibited favorable ADME and pharmacokinetic properties for further development. ER -