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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

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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/m2/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.

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Fig. 1
Fig. 2

Abbreviations

SNP:

Single nucleotide polymorphism

NPC:

Nasopharyngeal cancer

C max :

Peak plasma concentration

AUC0–inf :

Area under plasma concentration–time curve from time zero to infinity

CL:

Plasma clearance

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Acknowledgments

This study was supported by grants from National Medical Research Council, Singapore (NMRCB1011).

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore, 117597, Singapore

    Sin-Chi Chew & Edmund J. D. Lee

  2. Division of Medical Sciences, Laboratory of Clinical Pharmacology, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore

    Onkar Singh, Xiangai Chen, Rathi Devi Ramasamy, Tejal Kulkarni & Balram Chowbay

  3. Department of Medical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore

    Eng-Huat Tan & Wan-Teck Lim

Authors
  1. Sin-Chi Chew
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  2. Onkar Singh
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  3. Xiangai Chen
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  4. Rathi Devi Ramasamy
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  5. Tejal Kulkarni
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  6. Edmund J. D. Lee
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  7. Eng-Huat Tan
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  8. Wan-Teck Lim
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  9. Balram Chowbay
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Corresponding author

Correspondence to Balram Chowbay.

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Chew, SC., Singh, O., Chen, X. et al. 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 67, 1471–1478 (2011). https://doi.org/10.1007/s00280-011-1625-9

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  • DOI: https://doi.org/10.1007/s00280-011-1625-9

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