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

Xenobiotica. 2009 Apr;39(4):283-92. doi: 10.1080/00498250802714907.


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. 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 6alpha-hydroxypaclitaxel formation (IC((50)) = 2.1 +/- 0.2 muM), thus decreasing the metabolic elimination of paclitaxel. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Biotransformation / physiology
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Isoenzymes / metabolism
  • Kinetics
  • Mass Spectrometry
  • Microsomes, Liver / metabolism*
  • Molecular Structure
  • Oxidation-Reduction
  • Taxoids / chemistry
  • Taxoids / metabolism*
  • Taxoids / pharmacokinetics*


  • 7-epipaclitaxel
  • Isoenzymes
  • Taxoids
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human