Brivanib is a novel dual inhibitor for both VEGF and FGF signaling pathways that regulate angiogenesis and tumor cell proliferation. Brivanib alaninate, the oral alanine prodrug of brivanib, is currently in phase III clinical trials in hepatocellular carcinoma and colorectal cancer. Preclinical and clinical studies have demonstrated that brivanib was highly effective and well tolerated in humans. Brivanib has a single asymmetric center derived from a secondary alcohol with an R-configuration. The potential for chiral inversion was investigated in incubations with liver subcellular fractions, and in humans and animals following oral doses of brivanib alaninate. Incubation of [14C]brivanib alaninate with liver microsomes from rats, monkeys and humans in the presence of NADPH resulted in two radioactive peaks corresponding to brivanib and its enantiomer. The percent of the enantiomeric metabolite formed relative to brivanib ranged from 12-25% across species. Following oral doses of brivanib alaninate to humans, brivanib underwent minimal metabolic chiral inversion with the plasma concentration of the enantiomer less than 3% of brivanib concentration in humans. Following oral doses of brivanib alaninate to rats and monkeys, plasma concentration of the enantiomer ranged from 16-186% of brivanib concnetration. The proposed mechanism involves oxidation of brivanib to a ketone metabolite, followed by reduction to yield brivanib or its enantiomer.