Pharmacokinetics of the fluoropyrimidines: implications for their clinical use

There are four areas of current research interest in the fluoropyrimidines which may improve clinical utility of this class of drugs (Table 2). First, there is the obvious need for comprehensive pharmacokinetic information in man not only on the parent drug, be it 5FU, FUdR or ftorafur, but also on all potentially active metabolites. Second, knowledge of the distribution of uridine kinase, phosphoribosyl transferase and thymidine kinase in human bone marrow, gastrointestinal mucosa and accessible tumors would help clarify which of these enzymes controls 5-FU activation. Third, the availability of techniques to determine FdUMP formation within the target tumor cell provides an opportunity for predictive pharmacologic testing which should be fully exploited, especially in the adjuvant situation where tumor tissue is available and severe drug toxicity unacceptable. {A table is presented}. Finally, the greater lipid solubility and lessened marrow toxicity of ftorafur represents an improvement over 5-FU which may be counterbalanced by new and potentially serious neurotoxicity. For this reason, attempts should be made to synthesize new analos which lack this neurotoxicity, but which preserve both the increased lipid solubility and detreased marrow toxicity.