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Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
Karolinska University .
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2009 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 104, no 2, 130-137 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2009. Vol. 104, no 2, 130-137 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-16525DOI: 10.1111/j.1742-7843.2008.00351.xISI: 000262487400008PubMedID: 19143748Scopus ID: 2-s2.0-58449133201OAI: oai:DiVA.org:liu-16525DiVA: diva2:158136
Note

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

Available from: 2009-01-30 Created: 2009-01-30 Last updated: 2017-04-27Bibliographically approved

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Green, HenrikSöderkvist, PeterRosenberg, PerÅvall Lundqvist, ElisabethPeterson, Curt

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