Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans - toxicological implications

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  • Shindoh Hidetoshi
    Pre-clinical Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura Research Labs.
  • Nakano Kohnosuke
    Pre-clinical Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura Research Labs.
  • Yoshida Takemi
    Department of Biochemical Toxicology, School of Pharmacy, Showa University
  • Ishigai Masaki
    Pre-clinical Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura Research Labs.

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  • Comparison of in vitro metabolic conversion of capecitabine to 5-fluorouracil in rats, mice, monkeys and humans–toxicological implications

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Capecitabine is an oral anticancer prodrug which is converted to 5-fluorouracil (5-FU) via 3 enzymatic steps, these being 5’-deoxy-5-fluorocytidine (5’-DFCR), 5’-deoxy-5-fluorouridine (5’-DFUR), and finally 5-FU by carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TP), respectively. Because rats, mice and monkeys are used for preclinical safety studies, we investigated the in vitro conversion from capecitabine to 5-FU by hepatic and intestinal mucosal microsomes and cytosols, to compare their metabolic activity to that of humans. Capecitabine was hydrolyzed to 5’-DFCR in hepatic and intestinal mucosal microsomes in these animal species. In humans and monkeys, CLint (Vmax/Km) for the hydrolysis of capecitabine in intestine (expressed as µl/min/g tissue) was much lower than that in hepatic microsomes but, in rats and mice, CLint was higher in intestine than in liver. In humans and monkeys, similar Km values and inhibition patterns by tetrahydrouridine (THU) a CDA inhibitor, were observed in CDA activity of hepatic and intestinal cytosols. However, rats showed very low CDA activity and mice showed non-Michaelis-Menten kinetics and a different inhibition pattern by THU. Km values for TP activity were almost similar in rats, mice, monkeys and humans. In conclusion, it was confirmed that monkeys are a suitable animal model for the safety assessment of capecitabine in terms of metabolic enzymes and it was suggested that higher toxic incidences in mouse small intestine were related to high hydrolytic activity of capecitabine in the small intestine.

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