Pharmacokinetic Study of Capecitabine in Monkeys and Mice. Species Diffrences in Distribution of the Enzymes Responsible for its Activation to 5-FU.

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  • ONODERA Hideko
    Department of Preclinical Science, Nippon Roche Research Center, Nippon Roche K.K.
  • KURUMA Isami
    Department of Preclinical Science, Nippon Roche Research Center, Nippon Roche K.K.
  • ISHITSUKA Hideo
    Department of Oncology, Nippon Roche Research Center, Nippon Roche K.K.
  • HORII Ikuo
    Department of Preclinical Science, Nippon Roche Research Center, Nippon Roche K.K.

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  • Pharmacokinetic study of capecitabine in monkeys and mice; species differences in distribution of the enzymes responsible for its activation to 5-FU

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Abstract

Capecitabine, a new orally available fluorpyrimidine carbamate, is converted to 5-fluorouracil (5-FU) by three sequential reactions involving the enzymes carboxylesterase, cytidine (Cyd) deaminase, and pyrimidine nucleoside phosphorylase (PyNPase). In the present study the plasma level profiles of capecitabine and its metabolites were investigated after single and repeated oral administration to monkeys and mice. The activities of the three enzymes were also determined in several tissues of humans, monkeys, mice, and rats.<BR> Capecitabine was absorbed rapidly and converted to 5-FU in both monkeys and mice after a single oral dosing. The concentration of the intact drug and 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-FU were declined rapidly, as reflected by short half-lives of less than 1 hour in monkeys and 1-4 hours in mice. The AUCs of 5-FU were much lower than those of the intact drug and other metabolites, approximately 10 to 50-fold lower than that for 5'-DFUR expressed on a molar basis. In monkeys, the AUC and Cmax for capecitabine and its metabolites were dose related, and the AUC ratio for 5-FU to 5'-DFUR was independent of the dose. 5'-DFUR and the intact drug were prevalent in the plasma, and the 5'-DFCR level was slightly lower. In the monkey plasma, α-fluoro-β-alanine, a catabolite of 5-FU, was one of the main metabolites and showed relatively longer half-lives (5-7 hours). In mice, 5'-DFCR and the intact drug predominated in the plasma, and 5'-DFUR levels were lower than those.<BR> The AUCs of capecitabine, 5'-DFCR, and 5'-DFUR were dose related and similar in both genders during repeated daily oral dosing for 5 weeks in monkeys and mice. These values were not affected by repeated administration.<BR> The unique distribution of three 5-FU generating enzymes was found with interspecies deference. In humans, carboxylesterase was almost predominantly located in the liver. The monkey showed patterns of the enzyme activities that were the most similar to those in humans. In mice, the distribution patterns of carboxylesterase and Cyd deaminase were different from those in humans; however, mice have all three enzyme activities needed to generate 5-FU. On the contrary, in rats, extremely low Cyd deaminase activity was observed.<BR> The plasma level profiles of capecitabine and its metabolites were consistent with the observed activities of these enzymes in each species. Therefore, it seems that the monkey is the most suitable animal to use for predicting pharmacokinetics and safety of capecitabine in humans.

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