Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer.
We developed a population pharmacokinetic (PPK) model of S-1 including the cytochrome P450 (CYP) 2A6 genotype and then used this PPK model to assess the influence of the CYP2A6 genotype on PK parameters of S-1 and the relationship between toxicity and the individual maximum concentrations (Cmax) or the area under the concentration-time curve (AUC) of 5-fluorouracil (5-FU) in Japanese patients with advanced cancer. Fifty-eight patients with advanced cancer were assessed. A dose of 80 mg/m(2)/day of S-1 was given orally. On the basis of the CYP2A6 genotypes (*1, *4, *7 and *9), all patients were classified as having the wild-type, 1 variant allele or 2 variant alleles. The PPK model was established with plasma concentration data for tegafur (FT), 5-chloro-2,4-performed dihydroxypyridine (CDHP) and 5-FU. In patients with 2 variant alleles of CYP2A6, the clearance of FT was 58% less than in patients with the wild-type or 1 variant allele. The AUC of 5-FU correlated with the AUC of CDHP, but not with the AUC of FT. Therefore, the CYP2A6 genotype did not affect the AUC of 5-FU. The individual AUC or Cmax of 5-FU did not differ significantly between patients with grade 3 or 4 toxicities and patients with grade 0-2 toxicities. In conclusion, the CYP2A6 genotype did not affect the AUC of 5-FU, although the clearance of FT was lower in patients with 2 variant alleles of CYP2A6 than in patients with the wild-type or 1 variant allele.
Hirose
Takashi
T
Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, Shinagawa, Tokyo 142-8666, Japan. thirose@med.showa-u.ac.jp
Fujita
Ken-Ichi
K
Nishimura
Kazuko
K
Ishida
Hiroo
H
Yamashita
Keishi
K
Sunakawa
Yu
Y
Mizuno
Keiko
K
Miwa
Keisuke
K
Nagashima
Fumio
F
Tanigawara
Yusuke
Y
Adachi
Mitsuru
M
Sasaki
Yasutsuna
Y
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D065637:Cytochrome P-450 CYP2A6; D018450:Disease Progression; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D005641:Tegafur / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D005472:Fluorouracil