Metabolism of the anticancer drug taxol was investigated in freshly isolated rat hepatocytes. Two main metabolites were separated by reversed-phase HPLC and shown by tandem mass spectrometry to be monohydroxylated metabolites. Kinetic studies revealed apparent Km values of 68 and 61 μM with identical Vmax values for the two metabolites. Verapamil and midazolam, but not phenacetin, showed concentration-dependent inhibition of taxol metabolism with both metabolites being affected equally. The ic50 was about 100 μM for verapamil and 25 μM for midazolam. These observations demonstrate for the first time in vitro metabolism of taxol and suggest that the metabolism may be subject to potentially important interactions with numerous other drugs.
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