Methods:

Twelve healthy male volunteers received a single oral dose of 800 mg [14C]-DLV (100 μCi). Blood, plasma, urine, feces and saliva were collected for 6 to 10 days and analyzed for radioactivity. Metabolite profiling was performed using plasma, urine and fecal samples by radiochromatography, and metabolite identification was based on LC/MS/MS. Quantitation of DLV and its major plasma metabolites, was performed using synthetic standards. Exposure of the major metabolites in humans was compared to that in rats and mice. In vitro studies with recombinant CYP450 enzymes, UGT enzymes and gut bacteria were performed to identify enzymes responsible for the metabolism of DLV. Results: Mean selleck chemicals recovery of radioactivity was high (93.4% over 216 h). Most of the radioactivity was recovered

in feces (93.3%), with minimal excretion into urine (0.146%). DLV represented the major circulating species in plasma (∼63.0% of total AUC). There were two major circulating metabolites, BI 208333, an acyl glucuronide conjugate representing 20.2% of total AUC, and CD 6168, an alkene reduction metabolite, representing 15.3% of total AUC. DLV, BI 208333 and CD 6168 demonstrated similar time courses of plasma exposure, with median tmax values in the range of ∼3 to 6 h and geometric mean terminal half-life of ∼3 h. DLV and CD 6168 were also the predominant components buy ZD1839 in feces representing 30.4% and 34.6% of radioactivity dose, respectively. Other fecal metabolites included three hydroxylated metabolites, which are most likely secondary metabolites of CD 6168, each representing <10% of the radioactive dose. In vitro data indicated that UGT1 A1 was predominantly responsible for formation of BI 208333, whereas gut bacteria, but not microsomal or cytosolic hepatic enzymes, were responsible for the reduction of DLV to form CD 6168. Conclusions: DLV demonstrated good recovery and mass balance in healthy male volunteers. Two major circulating

metabolites of DLV were identified, BI 208333 and CD 6168, which had similar pharmacokinetic profiles to that of the parent. Both metabolites were adequately represented in the nonclinical toxicity studies. Metabolism and excretion into feces are to the major elimination routes for DLV. Disclosures: Lin-Zhi Chen – Employment: Boehringer Ingelheim Pharmaceuticals Sean Regan – Employment: Boehringer Ingelheim Pharmaceuticals Inc. Hongbin Yu – Employment: Boehringer Ingelheim Pharmaceuticals, Inc. John P. Sabo – Employment: Boehringer Ingelheim Pharmaceuticals, Inc. The following people have nothing to disclose: Rucha S. Sane, Elsy Philip, Hlaing Maw, Arti Mathur, Yongmei Li, Debra A. Mandarino Background: MK-5172, a reversible, noncovalent, competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is being developed for the treatment of chronic HCV infection.