Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism

Pharmacogenomics J. 2008 Aug;8(4):268-77. doi: 10.1038/sj.tpj.6500482. Epub 2007 Oct 9.

Abstract

Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype-genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6alpha-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c.521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0-infinity). Functional studies suggested -271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Aryl Hydrocarbon Hydroxylases / physiology
  • Carbamates / metabolism*
  • Carbamates / pharmacology
  • Cytochrome P-450 CYP2C8
  • European Continental Ancestry Group / genetics
  • Genetic Variation / drug effects
  • Genetic Variation / genetics
  • Haplotypes / drug effects
  • Haplotypes / genetics*
  • Humans
  • Paclitaxel / metabolism*
  • Paclitaxel / pharmacology
  • Piperidines / metabolism*
  • Piperidines / pharmacology

Substances

  • Carbamates
  • Piperidines
  • repaglinide
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Paclitaxel