Abstract
Abstract ARQ 736 is a highly-soluble phosphate prodrug that readily undergoes conversion to ARQ 680 in the presence of phosphatases. The active drug, ARQ 680, is a pan-RAF inhibitor that is effective, both in vitro and in vivo, in inhibiting proliferation of cancer cell lines expressing mutant-BRAF (V600E). During preclinical development, the metabolic fate of ARQ 736 and ARQ 680 was evaluated in human, rat, and dog in vitro systems. Based on the data generated, metabolic pathways were proposed for ARQ 736 and ARQ 680. Cross-species metabolic stability studies were conducted in microsomes and hepatocytes. CYP450 reaction phenotyping using 6 recombinant CYP isozymes was conducted to identify the CYP isozyme(s) responsible for the phase one metabolism of ARQ 736 and ARQ 680. ARQ 736 and ARQ 680 were incubated in hepatocytes and liver fractions to evaluate the phase one and phase two metabolites produced in humans rats, and dogs. Additional studies in microsomes and hepatocytes were conducted to evaluate the potential for ARQ 736 or ARQ 680 to inhibit or induce various CYP450 isozymes. Cross-species NADPH-dependent metabolism studies revealed that ARQ 736 and 680 were highly stable in, rat, dog, and human liver microsomes with half-life values >30 min. CYP450 reaction phenotyping indicated that CYP3A4 is the predominant CYP450 isozyme responsible for phase one metabolism of ARQ 736 and 680. Detailed metabolite ID work in hepatocytes identified multiple phase one and two metabolites as a result of oxidations, demethylation and glucuronidation. Metabolic pathways appeared to be similar across all species tested. In conclusion, this research is the first characterization of the metabolism of ARQ 736, a novel pan-RAF inhibitor currently being tested in phase one clinical trial in cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3231. doi:10.1158/1538-7445.AM2011-3231
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