The CYP2A64 Allele Is Determinant of S-1 Pharmacokinetics in Japanese Patients With Non-small-cell Lung Cancer

• Published in: Clinical pharmacology and therapeutics 2008-04, Vol.83 (4), p.589-594
• Main Authors: Kaida, Y, Inui, N, Suda, T, Nakamura, H, Watanabe, H, Chida, K
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alleles; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - therapeutic use; Area Under Curve; Aryl Hydrocarbon Hydroxylases - genetics; Asian Continental Ancestry Group - genetics; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - etiology; Carcinoma, Non-Small-Cell Lung - genetics; Cytochrome P-450 CYP2A6; Drug Combinations; Female; Fluorouracil - blood; Fluorouracil - pharmacokinetics; Genotype; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - etiology; Lung Neoplasms - genetics; Male; Middle Aged; Mixed Function Oxygenases - genetics; Oxonic Acid - pharmacokinetics; Oxonic Acid - therapeutic use; Smoking - adverse effects; Smoking - genetics; Smoking - metabolism; Tegafur - pharmacokinetics; Tegafur - therapeutic use
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/sj.clpt.6100484

S‐1 is an oral fluorouracil anticancer drug that contains the 5‐FU prodrug tegafur. Tegafur has been shown to be converted enzymatically to 5‐FU to exert its antitumor effect, and this conversion is principally catalyzed by CYP2A6. Forty‐six non‐small‐cell lung cancer patients were enrolled. The frequencies of the CYP2A6*4C, CYP2A6*7, and CYP2A6*9 alleles were 17.4, 19.6, and 15.2%, respectively. In the S‐1 pharmacokinetic analysis, the area under the concentration–time curve from 0 to 10 h (AUC0–10) ratios of 5‐FU/tegafur showed large interindividual variabilities, ranging from 5.14 to 112.6. The AUC0–10 for tegafur was 1.5‐fold higher in patients with the CYP2A6*4C allele than in patients without the CYP2A6*4C allele P < 0.05). Furthermore, patients with the CYP2A6*4C allele had a significantly lower maximum plasma concentration (102.6 ± 32.9 ng/ml) for 5‐FU than patients without the CYP2A6*4C allele (157.0 ± 65.5 ng/ml, P < 0.05). Genotyping of CYP2A6 polymorphisms may provide vital information for effective cancer therapy using S‐1. Clinical Pharmacology & Therapeutics (2008); 83, 4, 589–594. doi:10.1038/sj.clpt.6100484