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

AbstractPURPOSE:
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.
AuthorsSin-Chi Chew, Onkar Singh, Xiangai Chen, Rathi Devi Ramasamy, Tejal Kulkarni, Edmund J D Lee, Eng-Huat Tan, Wan-Teck Lim, Balram Chowbay
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 67 Issue 6 Pg. 1471-8 (Jun 2011) ISSN: 1432-0843 [Electronic] Germany
PMID21468756 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ABCB1 protein, human
  • ABCC2 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 Protein 2
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Taxoids
  • Docetaxel
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
Topics
  • 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, pharmacology, therapeutic use)
  • Asian People
  • Cytochrome P-450 CYP3A (genetics)
  • Docetaxel
  • Female
  • Humans
  • Male
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins (genetics)
  • Nasopharyngeal Neoplasms (drug therapy, genetics)
  • Neoplasm Proteins (genetics)
  • Organic Anion Transporters, Sodium-Independent (genetics)
  • Polymorphism, Single Nucleotide
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Taxoids (pharmacokinetics, pharmacology, therapeutic use)

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