Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel.

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Publication year
2006Source
Clinical Cancer Research, 12, 19, (2006), pp. 5786-5793ISSN
Publication type
Article / Letter to editor

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Organization
Condensed Matter Science (HFML)
Medical Oncology
Journal title
Clinical Cancer Research
Volume
vol. 12
Issue
iss. 19
Page start
p. 5786
Page end
p. 5793
Subject
ONCOL 3: Translational research; UMCN 1.1: Functional ImagingAbstract
PURPOSE: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. EXPERIMENTAL DESIGN: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. RESULTS: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (-25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified. CONCLUSIONS: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.
This item appears in the following Collection(s)
- Academic publications [205116]
- Electronic publications [103350]
- Faculty of Medical Sciences [81054]
- Faculty of Science [32353]
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