Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer
- 15 January 2009
- journal article
- research article
- Published by Wiley in Basic & Clinical Pharmacology & Toxicology
- Vol. 104 (2), 130-137
- https://doi.org/10.1111/j.1742-7843.2008.00351.x
Abstract
The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.Keywords
This publication has 43 references indexed in Scilit:
- Pharmacogenetic Assessment of Toxicity and Outcome After Platinum Plus Taxane Chemotherapy in Ovarian Cancer: The Scottish Randomised Trial in Ovarian CancerJournal of Clinical Oncology, 2007
- Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancerThe Pharmacogenomics Journal, 2007
- In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphismsPharmacogenetics and Genomics, 2006
- Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropeniaEuropean Journal of Cancer, 2006
- Measurement of paclitaxel and its metabolites in human plasma using liquid chromatography/ion trap mass spectrometry with a sonic spray ionization interfaceRapid Communications in Mass Spectrometry, 2006
- Genetic variation in ABCB1 influences paclitaxel pharmacokinetics in Japanese patients with ovarian cancerInternational Journal of Gynecologic Cancer, 2006
- mdr-1 Single Nucleotide Polymorphisms in Ovarian Cancer Tissue: G2677T/A Correlates with Response to Paclitaxel ChemotherapyClinical Cancer Research, 2006
- Phenotype–genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 allelesBiochemical and Biophysical Research Communications, 2005
- Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 Polymorphisms with the Pharmacokinetics of PaclitaxelClinical Cancer Research, 2005
- Use of Probe Drugs as Predictors of Drug Metabolism in HumansThe Journal of Clinical Pharmacology, 1997