Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer

Takashi Hirose, Ken Ichi Fujita, Kazuko Nishimura, Hiroo Ishida, Keishi Yamashita, Yu Sunakawa, Keiko Mizuno, Keisuke Miwa, Fumio Nagashima, Yusuke Tanigawara, Mitsuru Adachi, Yasutsuna Sasaki

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Abstract

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 concentrationtime 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/m2/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 wildtype, 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 wildtype 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.

Original languageEnglish
Pages (from-to)529-536
Number of pages8
JournalOncology Reports
Volume24
Issue number2
DOIs
Publication statusPublished - 2010

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Pharmacokinetics
Genotype
Area Under Curve
Fluorouracil
Tegafur
Alleles
Neoplasms
Population
Cytochrome P-450 Enzyme System

Keywords

  • Cancer
  • CYP2A6 genotype
  • Pharmacokinetics
  • S-1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Hirose, T., Fujita, K. I., Nishimura, K., Ishida, H., Yamashita, K., Sunakawa, Y., ... Sasaki, Y. (2010). Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer. Oncology Reports, 24(2), 529-536. https://doi.org/10.3892/or-00000889

Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer. / Hirose, Takashi; Fujita, Ken Ichi; Nishimura, Kazuko; Ishida, Hiroo; Yamashita, Keishi; Sunakawa, Yu; Mizuno, Keiko; Miwa, Keisuke; Nagashima, Fumio; Tanigawara, Yusuke; Adachi, Mitsuru; Sasaki, Yasutsuna.

In: Oncology Reports, Vol. 24, No. 2, 2010, p. 529-536.

Research output: Contribution to journalArticle

Hirose, T, Fujita, KI, Nishimura, K, Ishida, H, Yamashita, K, Sunakawa, Y, Mizuno, K, Miwa, K, Nagashima, F, Tanigawara, Y, Adachi, M & Sasaki, Y 2010, 'Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer', Oncology Reports, vol. 24, no. 2, pp. 529-536. https://doi.org/10.3892/or-00000889
Hirose T, Fujita KI, Nishimura K, Ishida H, Yamashita K, Sunakawa Y et al. Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer. Oncology Reports. 2010;24(2):529-536. https://doi.org/10.3892/or-00000889
Hirose, Takashi ; Fujita, Ken Ichi ; Nishimura, Kazuko ; Ishida, Hiroo ; Yamashita, Keishi ; Sunakawa, Yu ; Mizuno, Keiko ; Miwa, Keisuke ; Nagashima, Fumio ; Tanigawara, Yusuke ; Adachi, Mitsuru ; Sasaki, Yasutsuna. / Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer. In: Oncology Reports. 2010 ; Vol. 24, No. 2. pp. 529-536.
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abstract = "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 concentrationtime 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/m2/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 wildtype, 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 wildtype 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.",
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