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Genetic variation in ABCB1 influences paclitaxel pharmacokinetics in Japanese patients with ovarian cancer
  1. H. Yamaguchi*,,
  2. T. Hishinuma*,,
  3. N. Endo*,
  4. H. Tsukamoto*,
  5. Y. Kishikawa,
  6. M. Sato,
  7. Y. Murai,
  8. M. Hiratsuka,
  9. K. Ito§,
  10. C. Okamura§,
  11. N. Yaegashi§,
  12. N. Suzuki*,,
  13. Y. Tomioka*, and
  14. J. Goto*,
  1. * Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
  2. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan
  3. Department of Clinical Pharmaceutics, Tohoku Pharmaceutical University, Sendai, Japan
  4. § Department of Obstetrics and Gynecology, Graduate School of Medicine, Tohoku University, Sendai, Japan
  1. Address correspondence and reprint requests to: Junichi Goto, PhD, Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Email: jun-goto{at}pharm.med.tohoku.ac.jp

Abstract

Paclitaxel, an antineoplastic agent used for the treatment of ovarian cancer, is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8 and is excreted from cells by ATP-binding cassette (ABCB1) (multi-drug resistance [MDR1], P-glycoprotein). Expression of these proteins is regulated by pregnane X receptor (PXR). Although there are common genetic polymorphisms in the genes encoding these proteins, their effect on the clinical efficacy of paclitaxel is unclear. We therefore examined the relationship of the paclitaxel pharmacokinetics in 13 patients with ovarian cancer to polymorphisms in CYP2C8, CYP3A5, ABCB1, and PXR. We found high interindividual variability in the plasma concentrations of two metabolites, 6α-hydroxypaclitaxel and p-3′-hydroxypaclitaxel. All the patients were genotyped as CYP2C8*1/*1. Neither the CYP3A5 A6986G (CYP3A5*3) nor the PXR C-25385T alleles were associated with altered plasma concentrations of paclitaxel and its metabolites. ABCB1 T-129C, T1236C, and G2677(A,T), however, was associated with lower area under the plasma concentration–time curve (AUC) of paclitaxel. We also observed a significant correlation between the AUC (r = −0.721) or the total clearance of paclitaxel (CLtot) (r = 0.673) and the ABCB1 mutant allele dosage in each patient. Taken together, our findings suggest that interindividual variability in paclitaxel pharmacokinetics could be predicted by ABCB1 genotyping.

  • ABCB1
  • genetic polymorphisms
  • ovarian cancer
  • paclitaxel pharmacokinetics

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Footnotes

  • H. Tsukamoto is presently at Institute for Environmental and Gender Specific Medicine, Graduate School of Medicine, Juntendo University, Urayasu, Japan; and N. Suzuki is presently at Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan.

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