Comparison of the pharmacokinetics and pharmacodynamics of S-1 between Caucasian and East Asian patients

Cancer Sci. 2011 Feb;102(2):478-83. doi: 10.1111/j.1349-7006.2010.01793.x. Epub 2010 Dec 10.

Abstract

S-1 is an oral fluoropyrimidine anti-neoplastic agent that is converted by CYP2A6 to 5-fluorouracil (5FU). We prospectively studied the pharmacokinetics and pharmacodynamics of S-1 in two groups of East Asian and Caucasian patients with solid malignancy refractory to standard chemotherapy, or for which 5FU was indicated, to elucidate differences in relation to CYP2A6 genotype and phenotype. S-1 was given orally at 30 mg/m(2) b.i.d. for 14 days every 21 days. Dose normalized AUC(0-48 h) for tegafur (P = 0.05) and gimeracil (P = 0.036) were higher in East Asians; conversely, AUC(0-48 h) of fluoro-β-alanine was higher in Caucasians (P = 0.044). Exposure to 5FU was similar in both groups (P = 0.967). Mean cotinine:nicotine ratio was 54% higher in the Caucasian group (P = 0.03), and correlated with oral clearance of tegafur (r = 0.59; P = 0.002). Grade 3/4 gastrointestinal toxicities were more common in Caucasians than Asians (21%vs 0%). Treatment with S-1 yields no significant difference in 5FU exposure between Caucasians and East Asians.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Asia, Eastern
  • Asian People / genetics
  • Cytochrome P-450 CYP2A6
  • Drug Combinations
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy
  • Oxonic Acid / adverse effects
  • Oxonic Acid / pharmacokinetics*
  • Phenotype
  • Tegafur / adverse effects
  • Tegafur / pharmacokinetics*
  • White People / genetics

Substances

  • Antimetabolites, Antineoplastic
  • Drug Combinations
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6