Effects of CYP2A6 genotype and plasma level of 5-chloro-2,4-dihydroxipyridine (CDHP) on pharmacokinetics (PK) of tegafur (FT) and 5-fluorouracil (5-FU) in the patients treated by S-1

Abstract

2504 Background: S-1, which is an oral anticancer agent comprised of FT, CDHP and potassium oxonate, is one of the most widely prescribed agents in the treatment of gastric and colorectal cancer in Japan. CYP2A6 is involved in the bioactivation of FT to 5-FU. Dihydropyrimidine dehydrogenase which is responsible for the detoxification of 5-FU is inhibited by CDHP to increase plasma exposure of 5- FU. The dose of S-1 is determined by body surface area (BSA) of the patients. We prospectively analyzed contribution of CYP2A6 genotype, plasma level of CDHP, and BSA on the PK of FT and 5-FU. Methods: Forty Japanese patients with metastatic/ recurrent cancers who received S-1 were enrolled. Genetic polymorphisms in CYP2A6 (*4, *7 and *9) related to deficient or reduced activity were analyzed. CYP2A6 genotypes were defined as wild (*1/*1), one-reduced allele (*1/*4, *1/*7 or *1/*9) and two-reduced alleles (*4/*4, *4/*7, *4/*9, *7/*7, *7/*9 or *9/*9). On the first day of the treatment, plasma concentration of FT, 5-FU and CDHP were measured. Multivariate linear regression analysis was used identifying association or correlation between oral clearance (CL/F) for FT or area under the time-concentration curve (AUC) for 5-FU and possible factors including CYP2A6 genotype, AUC for CDHP and patient’s characteristics including BSA. Results: CL/F for FT was significantly associated with CYP2A6 genotype (ANOVA, P=0.0000787, R2=50.1%), but not with other factors. CL/F for FT in patients with one- and two-reduced allele(s) were significantly lower than that in wild patients (P=0.0126 and 0.000128, respectively; Wilcoxon test). AUC for 5-FU was significantly correlated with AUC for CDHP (ANOVA, P=0.000534, R2=39%), but not with others. AUC for CDHP was correlated with creatinine clearance (Ccr) (ANOVA, P=0.00056, R2=27.2%). Conclusions: PK of FT and 5-FU are significantly affected by CYP2A6 genotype and exposure of CDHP, respectively. In addition, AUC for CDHP, which is correlated with Ccr, is the more critical factor to regulate AUC for 5-FU than BSA. Ccr-based dosing will be more rational than the conventional BSA-based dosing in the prescription of S-1. No significant financial relationships to disclose.