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PHARMACOGENOMICS

Pharmacokinetics of Paclitaxel in Ovarian Cancer Patients and Genetic Polymorphisms of CYP2C8, CYP3A4, and MDR1

Miki Nakajima, PhD, Yuto Fujiki, MS, Satoru Kyo, MD, PhD, Taro Kanaya, MD, PhD, Mitsuhiro Nakamura, MD, Yoshiko Maida, MD, PhD, Masaaki Tanaka, MD, PhD, Masaki Inoue, MD, PhD and Tsuyoshi Yokoi, PhD

From Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences (Dr Nakajima, Ms Fujiki, Dr Yokoi), and the Department of Obstetrics and Gynecology, Graduate School of Medical Science (Dr Kyo, Dr Kanaya, Dr Nakamura, Dr Maida, Dr Tanaka, Dr Inoue), Kanazawa University, Kanazawa, Japan.

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/6{alpha}-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.

Key Words: Genetic polymorphism • cytochrome P450 • P-glycoprotein • pharmacokinetics

Address for reprints: Miki Nakajima, PhD, Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.




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