Pharmacology and pharmacokinetics of paclitaxel.

Abstract

There remain several pharmacologic considerations relating to paclitaxel that are being, or need to be, explored. Some of the more important of these include the following issues: Further elaboration of the metabolic fate of paclitaxel. A multicenter study is currently being planned to determine the complete metabolic fate of paclitaxel, using radiolabeled (14C) drug. Establishing criteria for optimal dosing and scheduling, particularly in patients with organ dysfunction. Evaluation of the optimal use of paclitaxel in combination with other drugs, and the potential interactions of these drugs, which may result in different response and toxicity patterns. Several aspects of drug-drug interactions are being considered. Interactions between paclitaxel and other drugs that are highly protein bound. Interactions with the P-450 enzyme system, in which antineoplastic agents that are currently used in combination with paclitaxel, such as cisplatin and doxorubicin, have been shown to modulate these enzymes. Interactions at the level of hepatic metabolism between paclitaxel and the H2-antagonists used as a premedication to prevent hypersensitivity reactions. Different compounds of this class, including cimetidine, ranitidine, and famotidine, have variable modulatory effects on P-450 enzymes. The choice of a specific agent may therefore affect response and toxicity patterns, although to date, no clinically significant drug interactions have been observed. Interactions between paclitaxel and other drugs used as supportive therapy that may inhibit P-450 enzymes. One such drug is erythromycin, which has been shown in a rat model to block significantly the excretion of doxorubicin through the MDR mechanism (unpublished data, J.G. Kuhn).(ABSTRACT TRUNCATED AT 250 WORDS)