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Pharmacokinetics of Paclitaxel in Ovarian Cancer Patients and Genetic Polymorphisms of CYP2C8, CYP3A4, and MDR1
Author(s) -
Nakajima Miki,
Fujiki Yuto,
Kyo Satoru,
Kanaya Taro,
Nakamura Mitsuhiro,
Maida Yoshiko,
Tanaka Masaaki,
Inoue Masaki,
Yokoi Tsuyoshi
Publication year - 2005
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270005276204
Subject(s) - paclitaxel , pharmacokinetics , ovarian cancer , cyp2c8 , cyp3a4 , oncology , medicine , pharmacology , chemotherapy , biology , cancer , cytochrome p450 , metabolism
Interindividual differences in the pharmacokinetics of paclitaxel and its metabolites in Japanese ovarian cancer patients were investigated in relation to genetic polymorphisms of the CYP2C8,CYP3A4 , and MDR1 genes. The area under the concentration‐time curve (AUC) ratios of paclitaxel/6α‐hydroxypaclitaxel and paclitaxel/3′‐ p ‐hydroxypaclitaxel calculated as the metabolic index of CYP2C8 and CYP3A4 showed 13‐ and 12‐fold interindividual variations, respectively. No patient had any CYP2C8 variants, while 2 patients were heterozygotes of CYP3A4*16. For the MDR1 gene, the frequencies of −129C, 1236C, 2677T, 2677A, and 3435T alleles were 2.2%, 8.7%, 56.5%, 4.4%, and 52.2%, respectively. Subjects possessing the 3435T allele had a significantly ( P < .05) higher AUC of 3′‐ p ‐hydroxypaclitaxel compared to those possessing the 3435C allele. Leukocytopenia was significantly ( P < .05) related to the AUC of paclitaxel. Genotyping of the CYP2C8, CYP3A4 , and MDR1 genes might not be essential to predict adverse effects of paclitaxel in Japanese patients, although an allelic variant of MDR1 may functionally affect the pharmacokinetics of its metabolite.