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.
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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 |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 67
Issue 6
Pg. 1471-8
(Jun 2011)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 21468756
(Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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