The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients

Cancer Chemother Pharmacol. 2011 Jun;67(6):1471-8. doi: 10.1007/s00280-011-1625-9. Epub 2011 Apr 6.

Abstract

Purpose: This exploratory study aimed to explain the interindividual variabilities of docetaxel pharmacokinetics and pharmacodynamics in Asian nasopharyngeal carcinoma patients (n = 54) through the genotyping of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 genes.

Methods: Docetaxel was administered over 1 h on days 1, 8, and 15 every 28 days at 30 mg/m(2)/dose. Genomic DNA was isolated from peripheral blood and genotyped for the selected polymorphisms in the candidate genes. Docetaxel pharmacokinetic parameters were estimated by non-compartmental modelling.

Results: Patients homozygous for the variant allele (GG) of SLCO1B3 rs11045585 (IVS12-5676A > G) had significantly higher area under the plasma concentration-time curve of docetaxel (P = 0.026) and lower clearance (P = 0.036) compared to patients with AA/AG genotypes. Patients harbouring the heterozygous genotype (GA + GT + TA) for ABCB1 rs2032582 (2677G > T/A) had the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with GG/TT genotypes (P = 0.006). Similar trend was observed for ABCB1 rs1045642 (3435C > T) with heterozygotes (CT) having the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with CC/TT genotypes (P = 0.066).

Conclusions: This study suggests that the cooperative influence of functional polymorphisms in SLCO1B3 and ABCB1 genes may be responsible for the interindividual variability in docetaxel disposition in Asian nasopharyngeal cancer patients.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Asian Continental Ancestry Group
  • Cytochrome P-450 CYP3A / genetics*
  • Docetaxel
  • Female
  • Humans
  • Male
  • Multidrug Resistance-Associated Proteins / genetics*
  • Nasopharyngeal Neoplasms / drug therapy*
  • Nasopharyngeal Neoplasms / genetics
  • Neoplasm Proteins / genetics*
  • Organic Anion Transporters, Sodium-Independent / genetics*
  • Polymorphism, Single Nucleotide
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Taxoids / pharmacokinetics
  • Taxoids / pharmacology*
  • Taxoids / therapeutic use

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Taxoids
  • Docetaxel
  • multidrug resistance-associated protein 2
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human