The CYP2A6*4 allele is determinant of S-1 pharmacokinetics in Japanese patients with non-small-cell lung cancer.
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 (AUC(0-10)) ratios of 5-FU/tegafur showed large interindividual variabilities, ranging from 5.14 to 112.6. The AUC(0-10) 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.
Kaida
Y
Y
The Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Inui
N
N
Suda
T
T
Nakamura
H
H
Watanabe
H
H
Chida
K
K
D000328:Adult; D000368:Aged; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D065637:Cytochrome P-450 CYP2A6; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010094:Oxonic Acid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D005641:Tegafur / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D005472:Fluorouracil