Pharmacogenetic pathway analysis of docetaxel elimination

Clin Pharmacol Ther. 2009 Feb;85(2):155-63. doi: 10.1038/clpt.2008.95. Epub 2008 May 28.

Abstract

The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. Among the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. None of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). However, the simultaneous presence of the CYP3A4*1B and CYP3A5*1A alleles was associated with a 64% increase in docetaxel clearance (P = 0.0015), independent of both sex and CYP3A activity (as determined using the erythromycin breath test). This haplotype was also associated with increased midazolam clearance in another population (P = 0.0198). An analysis of the CYP3A locus among CEPH-HapMap samples revealed that CYP3A4*1B is present exclusively among a subset of CYP3A5 expressors. Therefore, future studies should first stratify the population on the basis of CYP3A5 genotype and then compare CYP3A activity between individuals with and without the CYP3A4*1B allele.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Line
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Docetaxel
  • Dogs
  • Female
  • Gene Frequency / drug effects
  • Gene Frequency / physiology
  • Genetic Variation / drug effects
  • Genetic Variation / physiology
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Metabolic Clearance Rate / drug effects
  • Metabolic Clearance Rate / physiology
  • Middle Aged
  • Pharmacogenetics / methods*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Taxoids / metabolism*
  • Taxoids / pharmacokinetics
  • Taxoids / pharmacology*
  • Xenopus laevis
  • Young Adult

Substances

  • Membrane Transport Proteins
  • Taxoids
  • Docetaxel
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A