Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1.
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/6alpha-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.
Nakajima
Miki
M
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Fujiki
Yuto
Y
Kyo
Satoru
S
Kanaya
Taro
T
Nakamura
Mitsuhiro
M
Maida
Yoshiko
Y
Tanaka
Masaaki
M
Inoue
Masaki
M
Yokoi
Tsuyoshi
T
D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019450:Genes, MDR / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007206:Individuality; D007262:Infusions, Intravenous; D007564:Japan / Q000208:ethnology; D007970:Leukopenia / Q000139:chemically induced; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000502:physiology; D013921:Thrombocytopenia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C104464:CYP3A protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel