Summary: 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.
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 ba sis. In monkeys, the AUC and C_max for capecitabine and its metabolites were dose related, and the AUC ra tio 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.
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 ad ministration.
The unique distribution of three 5-FU generating enzymes was found with interspecies deference. In hu mans, 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 carbox ylesterase and Cyd deaminase were different from those in humans; however, mice have all three enzyme ac tivities needed to generate 5-FU. On the contrary, in rats, extremely low Cyd deaminase activity was ob served.
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.

-Drug-induced QT interval prolongation is a critical issue in development of new chemical entities, so the pharmaceutical industry needs to evaluate risk as early as possible. Common marmosets have been in the limelight in early-stage development due to their small size, which requires only a small amount of test drug. The purpose of this study was to determine the utility of telemetered common marmosets for predicting drug-induced QT interval prolongation. Telemetry transmitters were implanted in common marmosets (male and female), and QT and RR intervals were measured. The QT interval was corrected for the RR interval by applying Bazett's and Fridericia's correction formulas and individual rate correction. Individual correction showed the least slope for the linear regression of corrected QT (QTc) intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. In conclusion, telemetry studies in common marmosets are useful for predicting clinical QT prolonging potential of drugs in early stage development and require only a small amount of test drug.

Catechol-O-methyltransferase (COMT) catalyses the transfer of the methyl group from S-adenyl-L-methionine (SAM) to one of the hydroxy groups of a catechol, usually the hydroxy group in position 3. COMT is present mainly in a soluble form (S-COMT) in the cytosol, but a small fraction is bound to cell membranes (MB-COMT). MB-COMT has higher affinity for the catechol substrate than does S-COMT by a factor of > 10, and high MB-COMT activity is observed in the intestinal muscle layer. The present study investigates the effect of the administration route on the disposition of the tolcapone 3-O-methylated metabolite following intravenous and oral tolcapone administration in rats. Tolcapone is a substrate for COMT although the 3-O-methylated metabolite produced has no pharmacological actions. The 3-O-methylated metabolite was eliminated very slowly following oral administration of tolcapone, and its concentration approached a plateau level, which was in contrast to the situation following intravenous administration of tolcapone. It is thought that the oral dose of tolcapone receives a high exposure to MB-COMT in the intestinal muscle layer during its absorption, and tolcapone seems to form a complex with MB-COMT having a high affinity constant (i.e. a very low Ki). The fraction of the intravenous dose of tolcapone metabolized to the 3-O-methylated metabolite at 10 mg kg-1 was 2.6%, whereas those of the oral doses, which were corrected by the bioavailability, were 5.4% for 20 mg kg-1 and 2.7% for 40 mg kg-1.

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The effect of Madopar (benserazide and L-dopa, 1:4) on the disposition of the new selective inhibitor of catechol-O-methyltransferase, tolcapone, in rats was investigated. There was no statistically significant difference in the pharmacokinetic parameters of tolcapone in the presence or absence of Madopar except for a change in the mean residence time after oral administration. Thus, we rejected the hypothesis that the consumption of S-adenyl-L-methionine by Madopar would change the disposition of tolcapone. There were no statistically significant differences in the cumulative amount absorbed of drug and the absorption rate in the presence or absence of Madopar. We concluded that there was no interaction between tolcapone and Madopar.