Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer |
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| Authors: | Henrik Gréen Peter Söderkvist Per Rosenberg Rajaa A Mirghani Per Rymark Elisabeth Åvall Lundqvist Curt Peterson |
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| Institution: | 1. Division of Drug Research, Faculty of Health Sciences, Link?ping University, Link?ping,;2. Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Link?ping University, Link?ping,;3. Department of Oncology, Link?ping University Hospital, Link?ping,;4. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm,;5. Present affiliation: Department of Clinical Toxicology, Central Laboratories & Blood Bank, King Fahad Medical City, Riyadh 11525, Kingdom of Saudi Arabia.;6. Department of Obstetrics and Gynaecology, Central Hospital, V?ster?s, and;7. Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Solna, Stockholm, Sweden |
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| Abstract: | 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. |
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