ABSTRACT
Pharmacokinetic investigations are an integral part of drug development. There are also many applications for therapeutic drug monitoring for individualization of treatment. Antimetabolites, and among them the purine nucleoside analogs fludarabine and cladribine, illustrate these problems. They are prodrugs and need intracellular phosphorylation by kinases to form the intracellular active metabolites. A number of investigators have studied the plasma pharmacokinetics of fludarabine after intravenous bolus injection, short intravenous infusion, and continuous infusion. It is important to emphasize that the interindividual variability of the cellular pharmacokinetics of fludarabine triphosphate is pronounced compared with the plasma pharmacokinetics. The pharmacokinetics of pentostatin has therefore not been studied to the same extent as for fludarabine and cladribine. The intracellular pharmacokinetics of the total cladribine nucleotide pool has been described in hairy cell, chronic lymphocytic and acute myelogenous leukemias after intravenous, oral, and subcutaneous administration.
