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 basis. In monkeys, the AUC and C_max 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.
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.
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.
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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Recently, an increasing number of pharmaceutical scientists and clinical pharmacists have begun to focus on pharmacodynamics, which relates the time course of drug concentration to the time course of pharmacological effects. An integration knowledge of pharmacokinetics and pharmacodynamics is essential for the development of rational pharmacotherapeutics because pharmacodynamics and pharmacokinetics are able to determines the drug concentration required to produce the desired therapeutic effect and the drug dose regimen required to achieve the targeted drug concentration, respectively, by using various models. The general principles of the drug effect model are based on the reversible direct and indirect models. In this review, various models in terms of the time course of drug effects are presented and discussed.

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The clinical significance of the changing of plasma protein binding of drug was discussed. Blood concentration of free drug equilibrated with that at the site of action can be used as a useful tool for monitoring pharmacotherapy. The significant increase of blood concentration of free drug may be produced in a very restricted case which is described in detail in this article. However, it should be emphasized that the changing of concentration of total drug in blood does not parallel with that of free drug. Although the changing of plasma protein binding seems to be a minor factor in most of clinical cases, we should notice the role of protein binding which covers the changing of free drug when the monitoring using total drug concentration is performed.

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Pharmacokinetics is no longer considered to be a stand-alone discipline, but rather has become an integral factor contributing to assessment of the efficacy, interaction, and adverse reaction of drugs at clinical practice. Accordingly, it is important for the health care professionals, such as physicians and pharmacists, to get the sufficient pharmacokinetic data concerning the prescribed drugs for rational pharmacotherapy. Although the most basic tool for getting information on drugs is package inserts, many health care professionals has lack information on pharmacokinetics from it. It was suggested that more information on pharmacokinetics should be available in package inserts. The following are important pharmacokinetic parameters of drugs that must be expected from pharmacokinetic studies and listed in package inserts: (1) mass balance, (2) pharmacokinetics of active compound, (3) elimination rate and pathways (including data on metabolism, renal excretion and bilary excretion), (4) metabolic organ and enzyme (including data on metabolic interaction), (5) bioavailability (including data on absorption, first-pass effect and food effect), (6) time of half elimination and clearance, (7) single and repeated dose pharmacokinetics (including data on accumulation and linialyty), (8) plasma protein binding, (9) distribution to effective and toxic tissue, (10) pharmacokinetics under special conditions (including data on young, elderly, pregnant, renal disease, and hepatic disease).

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Pharmacokinetic and pharmacodynamic information of a newly developed drug is indispensable for draw up an appropriate dosing scheme. Such information obtained from healthy subjects and patients through clinical trials conducted in a current framework of Good Clinical Practice (GCP) during the pre-approval period may be applicable to the majority of patients who are to be administered the drug after approval. However, the current framework of GCP may not necessarily allows to conduct clinical trials in patients having altered pharmacokinetics and dynamics (e.g., those who possess impaired drug elimination organs, elderly and pediatric patients). They consist of the minority of patient population who required individualized drug therapy. A lack of information about fundamental pharmacokinetic parameters that are only obtainable by intravenous administration of drugs often makes it difficult to draw up an appropriate dosage scheme for patients having hepatic impairments particularly for drugs that are eliminated principally through hepatic metabolism. While abundant and ambiguous in vitro information have been generated regarding the potential impacts of pharmacogentic polymorphisms of drug metabolizing enzymes and metabolic drug interactions on the efficacy and developments of serious adverse drug reactions, few post-marketing clinical trials have been conducted for confirming in vivo consequences for the implications advocated by the in vitro studies. In this context, implementation of post-marketing clinical trials that would uncover altered pharmacokinetics and dynamics of patients due to hepatic impairments, aging, pharmacogenetic polymorphisms of drug metabolizing enzymes and metabolic drug interactions should be strongly encouraged.

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The Symposium: Mechanism-based Pharmacokinetics and Pharmacodynamics—Future Perspectives—was held on the occasion of the 25 th anniversary of appointment of Douwe D. Breimer as full Professor of Pharmacology at Leiden University. The advances of PK/PD study have been providing the great impacts on drug discovery and development. I would like to briefly introduce the contents of this attractive symposium.

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