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01-06-2011 | Short Communication

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

Authors: Sin-Chi Chew, Onkar Singh, Xiangai Chen, Rathi Devi Ramasamy, Tejal Kulkarni, Edmund J. D. Lee, Eng-Huat Tan, Wan-Teck Lim, Balram Chowbay

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2011

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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Title: The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients
Authors: Sin-Chi Chew
Onkar Singh
Xiangai Chen
Rathi Devi Ramasamy
Tejal Kulkarni
Edmund J. D. Lee
Eng-Huat Tan
Wan-Teck Lim
Balram Chowbay
Publication date: 01-06-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1625-9

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