Preclinical pharmacokinetics of paclitaxel and docetaxel

The taxanes paclitaxel and docetaxel represent a novel class of antineoplastic agents. A major problem of both drugs is their low aqueous solubility and the design of suitable formulations has been a difficult step in the process of therapeutic development. The formulations currently used are mixtures of Cremophor EL:ethanol for paclitaxel (Taxol(R)) and Tween 80:ethanol for docetaxel (Taxotere(R)), but many new approaches have been tested or are under investigation. Paclitaxel and docetaxel have a similar mechanism of action, which is based on promotion of tubulin assembly and inhibition of microtubule disassembly. Pharmacokinetic studies revealed a marked non-linearity of paclitaxel in mice, which appeared to result exclusively from Cremophor EL, the major component present in the pharmaceutical formulation. An almost linear pharmacokinetic behavior was observed in the case of docetaxel. The reported plasma protein binding of both compounds ranged from 76 to 97% in different animal species. Paclitaxel and docetaxel widely distribute into most tissues of mice and rats, including tumor tissue, but only low concentrations were detected in the central nervous system. Despite the great similarity in the chemical structures of paclitaxel and docetaxel, their metabolic profile is very distinct. Furthermore, whereas paclitaxel metabolism is largely species dependent, docetaxel metabolism is similar across species in both isolated hepatic microsomal fractions and in vivo models. For both taxanes, hepatobiliary excretion is the major pathway of elimination and a major fraction of the dose is excreted in feces as parent drug or hydroxylated metabolites. [(C) 1998 Rapid Science Ltd.].