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 |
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Authors: | Fujita Ken-ichi Yamamoto Wataru Endo Shoji Endo Hisashi Nagashima Fumio Ichikawa Wataru Tanaka Ryuhei Miya Toshimichi Araki Kazuhiro Kodama Keiji Sunakawa Yu Narabayashi Masaru Miwa Keisuke Ando Yuichi Akiyama Yuko Kawara Kaori Kamataki Tetsuya Sasaki Yasutsuna |
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Institution: | Department of Medical Oncology, Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298;;Project Research Laboratory, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan |
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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. ( Cancer Sci 2008; 99: 1049–1054) |
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