Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1

J Clin Pharmacol. 2005 Jun;45(6):674-82. doi: 10.1177/0091270005276204.

Abstract

Interindividual differences in the pharmacokinetics of paclitaxel and its metabolites in Japanese ovarian cancer patients were investigated in relation to genetic polymorphisms of the CYP2C8, CYP3A4, and MDR1 genes. The area under the concentration-time curve (AUC) ratios of paclitaxel/6alpha-hydroxypaclitaxel and paclitaxel/3 -p-hydroxypaclitaxel calculated as the metabolic index of CYP2C8 and CYP3A4 showed 13- and 12-fold interindividual variations, respectively. No patient had any CYP2C8 variants, while 2 patients were heterozygotes of CYP3A4*16. For the MDR1 gene, the frequencies of -129C, 1236C, 2677T, 2677A, and 3435T alleles were 2.2%, 8.7%, 56.5%, 4.4%, and 52.2%, respectively. Subjects possessing the 3435T allele had a significantly (P < .05) higher AUC of 3'- p-hydroxypaclitaxel compared to those possessing the 3435C allele. Leukocytopenia was significantly (P < .05) related to the AUC of paclitaxel. Genotyping of the CYP2C8, CYP3A4, and MDR1 genes might not be essential to predict adverse effects of paclitaxel in Japanese patients, although an allelic variant of MDR1 may functionally affect the pharmacokinetics of its metabolite.

Publication types

  • Clinical Trial
  • Comparative Study

MeSH terms

  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / drug effects
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Chromatography, High Pressure Liquid / methods
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Female
  • Genes, MDR / drug effects*
  • Genes, MDR / genetics
  • Humans
  • Individuality
  • Infusions, Intravenous
  • Japan / ethnology
  • Leukopenia / chemically induced
  • Metabolic Clearance Rate / drug effects
  • Metabolic Clearance Rate / genetics
  • Middle Aged
  • Nausea / chemically induced
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Paclitaxel / analogs & derivatives
  • Paclitaxel / metabolism
  • Paclitaxel / pharmacology*
  • Paclitaxel / therapeutic use
  • Polymorphism, Genetic / drug effects
  • Polymorphism, Genetic / physiology
  • Thrombocytopenia / chemically induced
  • Vomiting / chemically induced

Substances

  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Paclitaxel