title: CYP2A6 and the plasma level of 5-chloro-2, 4-dihydroxypyridine are determinants of the pharmacokinetic variability of tegafur and 5-fluorouracil, respectively, in Japanese patients with cancer given S-1.
abstract: S-1 is an oral anticancer agent composed of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. CDHP is added to prevent degradation of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase. CYP2A6 is involved in the biotransformation of FT to 5-FU. Thus, we prospectively analyzed the effects of the CYP2A6 genotype, plasma level of CDHP, and patient characteristics on the pharmacokinetic (PK) variability of FT and 5-FU. Fifty-four Japanese patients with metastatic or recurrent cancers who received S-1 were enrolled. The CYP2A6 polymorphisms (*4A, *7, and *9) with deficient or reduced activity were analyzed. All subjects were classified into three groups according to their CYP2A6 genotype: wild type (*1/*1), one-variant allele (*1/any), or two-variant alleles (combination other than *1). The PK of FT, 5-FU, and CDHP were measured on day 1 of treatment. Multivariate regression analysis revealed that oral clearance of FT was associated with the CYP2A6 genotype (analysis of variance [ANOVA], P = 0.000838). The oral clearance of FT seen in patients with the two-variant alleles was significantly lower than those in wild type and the one-variant allele (95% confidence intervals 0.75-2.41 and 0.41-1.82, respectively; Tukey-Kramer test). The area under the time-concentration curve (AUC) of 5-FU was significantly correlated with the AUC of CDHP (ANOVA, P = 0.00126). The AUC of 5-FU and CDHP were inversely correlated with creatinine clearance (ANOVA, P = 0.0164 and P = 0.000762, respectively). Although the CYP2A6 variants are the cause of the PK variability of FT, the AUC of CDHP affected by renal function is the key determinant of the variability in the PK of 5-FU.
authors.affiliation: Department of Medical Oncology, Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Endo
authors.forename: Hisashi
authors.initials: H
authors.lastname: Endo
authors.forename: Fumio
authors.initials: F
authors.lastname: Nagashima
authors.forename: Wataru
authors.initials: W
authors.lastname: Ichikawa
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Tanaka
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Miya
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Araki
authors.forename: Keiji
authors.initials: K
authors.lastname: Kodama
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Narabayashi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miwa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
authors.forename: Yuko
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Kaori
authors.initials: K
authors.lastname: Kawara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kamataki
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People; D065637:Cytochrome P-450 CYP2A6; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D010094:Oxonic Acid / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000097:blood*; D005641:Tegafur / Q000493:pharmacokinetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; 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; C104201:gimeracil