Drug interactions with the taxanes.

Interactions may occur when the taxanes paclitaxel and docetaxel are given concurrently with other drugs. Altered clearance may be expected because these agents are extensively metabolized by hepatic cytochrome P-450 enzymes, particularly isoenzymes 3A and 2C. Pharmacodynamic interactions that alter the molecular target or pharmacology of a drug may depend on the sequence or schedule of administration. Paclitaxel clearance is reduced when cisplatin precedes paclitaxel, although cisplatin does not affect the metabolism of paclitaxel by human liver microsomes. Measurement of DNA adduct levels in peripheral white blood cells indicates that a pharmacodynamic interaction may occur between cisplatin and both taxanes. The pharmacokinetics of carboplatin and paclitaxel were not altered when the drugs were given in combination; however, a pharmacodynamic interaction may explain the decreased frequency of thrombocytopenia compared with single-agent carboplatin. When paclitaxel precedes cyclophosphamide, myelosuppression is more severe. In contrast, when docetaxel precedes ifosfamide, toxicity is reduced. The mechanisms for these effects is unknown. With combination paclitaxel and doxorubicin regimens, the schedule of paclitaxel and the sequence of the agents may result in both pharmacokinetic and pharmacodynamic interactions.