Characterization of human cytochrome P450 isoforms involved in the metabolism of 7-epi-paclitaxel

Abstract

1. The C-7 chiral centre in paclitaxel is subject to epimerization under physiological conditions, thus making 7-epi-paclitaxel as the principal degradant. This study was designed to characterize the cytochrome P450 (CYP) enzymes involved in 7-epi-paclitaxel metabolism, and to examine possible metabolic interactions that this C-7 epimer may have with paclitaxel.

2. In human liver microsomes, 7-epi-paclitaxel was oxidized to two monohydroxylated metabolites while the metabolic sites occurred at the C-13 side-chain for M-1 and taxane core ring for M-2. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs, and enzyme kinetics indicated that M-1 was generated predominantly by CYP3A4 and M-2 by CYP2C8. Co-incubation of 7-epi-paclitaxel with paclitaxel in human liver microsomes resulted in potent inhibition of 6α-hydroxypaclitaxel formation (IC₅₀ = 2.1 ± 0.2 μM), thus decreasing the metabolic elimination of paclitaxel.

3. In conclusion, both CYP3A4 and CYP2C8 play a major role in biotransformation of 7-epi-paclitaxel in human liver microsomes. The existence of epimeric interactions between paclitaxel and its degradant might be a noteworthy factor resulting in the complex pharmacokinetic profile of paclitaxel.

Keywords::

• 7-Epi-paclitaxel
• paclitaxel
• cytochrome P450
• microsomes
• metabolism

Acknowledgements

This work was supported by the 973 Program (2009CB522808) of the Ministry of Science and Technology of China, the National Key Technology R&D Program in the 11th Five year Plan of China (2008ZX10208), the National Natural Science Foundation of China (30772608), and the Dalian Institute of Chemical Physics Innovation Fund of Chinese Academy of Sciences.

Declaration of interest: The authors state no conflict of interest.