Pharmacogenetic studies of Paclitaxel in the treatment of ovarian cancer
| Autor: | Henrik Gréen, Per Rosenberg, Carsten Peterson, Peter Söderkvist, Rajaa A. Mirghani, Per Rymark, Elisabeth Åvall Lundqvist |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
ATP Binding Cassette Transporter Subfamily B Paclitaxel medicine.medical_treatment Pilot Projects Pharmacology Biology Toxicology Polymerase Chain Reaction Polymorphism Single Nucleotide Drug Administration Schedule Carboplatin Cytochrome P-450 CYP2C8 Pharmaceutical Sciences chemistry.chemical_compound Pharmacokinetics Antineoplastic Combined Chemotherapy Protocols medicine Cytochrome P-450 CYP3A Humans ATP Binding Cassette Transporter Subfamily B Member 1 CYP2C8 Aged DNA Primers Ovarian Neoplasms Chemotherapy General Medicine DNA Middle Aged Farmaceutiska vetenskaper medicine.disease chemistry Toxicity Female Aryl Hydrocarbon Hydroxylases Ovarian cancer Pharmacogenetics |
| Zdroj: | Basicclinical pharmacologytoxicology. 104(2) |
| ISSN: | 1742-7843 |
| Popis: | 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. This is the authors’ version of the following article: Henrik Green, Peter Söderkvist, Per Rosenberg, Rajaa A Mirghani, Per Rymark, Elisabeth Avall Lundqvist and Curt Peterson, Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer, 2009, Basic and clinical pharmacology and toxicology, (104), 2, 130-137. which has been published in final form at: http://dx.doi.org/10.1111/j.1742-7843.2008.00351.x Copyright: Blackwell Publishing http://eu.wiley.com/WileyCDA/Brand/id-35.html |
| Databáze: | OpenAIRE |
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