Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients

Cancer Chemother Pharmacol. 2010 May;66(1):95-105. doi: 10.1007/s00280-009-1138-y. Epub 2009 Sep 22.

Abstract

Purpose: Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to "UGT1A1*28 or *6" on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated.

Methods: Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time-concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan-cisplatin-combination therapy (62 patients).

Results: Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ((#) IIB) and SLCO1B1 521T>C (V174A) (*15 x 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 (#) IIB, SLCO1B1*15 x 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory.

Conclusions: Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Asian Continental Ancestry Group / genetics
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacokinetics
  • Genotype
  • Glucuronosyltransferase / genetics*
  • Haplotypes
  • Humans
  • Irinotecan
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Neutropenia / chemically induced
  • Neutropenia / genetics
  • Organic Anion Transporters / genetics*
  • Polymorphism, Single Nucleotide*

Substances

  • Organic Anion Transporters
  • Irinotecan
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Cisplatin
  • Camptothecin