Development of Drug Monitoring System in Determining Optimal Dosage of Anticancer Drugs

为了建立抗癌药物最佳剂量的药代动力学监测系统，我们首先建立了基于TaqMan聚合酶链式反应的细胞色素P450(Gyp)2D6^*10、细胞色素P3A5^*3和细胞色素P3A5^*6等位基因多态性的快速诊断方法，并对引起多西他赛和S-1药代动力学个体差异的因素进行了研究。所有受试者均获得书面知情同意。CYP2D6基因分型结果显示，杂合子和纯合子的频率分别为43%和23%。CYP3A5基因分型结果显示，CYP3A5^*L/^*3(杂合子)和CYP3A5^*3/^*3(纯合子)的频率分别为45%和50%。结果表明，这些都是日语中常见的变体。13例非小细胞肺癌患者的多西紫杉醇药代动力学与CYP3A5基因分型无关。α-1-酸性糖蛋白浓度和血药浓度-时间曲线下面积是决定多西紫杉醇疗效和毒性的更重要的因素。对口服抗癌药S-1进行了群体药代动力学和药效学分析。5-氟尿嘧啶(5-FU)的血药浓度受DPD抑制剂吉美拉星的血药浓度影响。肾功能不全被发现是S-1毒性的一个危险因素，因为吉美拉西的延迟排泄导致更高的5-FU暴露。与日本患者相比，西方患者发生胃肠道毒性(腹泻)的频率更高，与男性相比，女性患者发生胃肠道毒性(腹泻)的频率更高。本研究结果将为抗癌药物的安全和最佳剂量提供依据。

To develop the pharmacokinetic monitoring system in determining an optimal dosage of anticancer drugs, we have firstly established a rapid diagnosis method based upon the TaqMan PCR allelic discrimination assay for genetic polymorphisms of cytochrome P450 (GYP) 2D6^*10, CYP3A5^*3 and CYP3A5^*6 alleles, then we have investigated the factors causing the individual variability in pharmacokinetics of docetaxel and S-1.Blood samples from 93 unrelated volunteers and 104 patients were collected for genotyping. The written informed consent was obtained from all subjects. The results of genotyping for CYP2D6 indicated that the frequency of CYP2D6^*1/^*10 (heterozygote) and CYP2D6^*10/^*10 (homozygote) were 43% and 23%, respectively. The results of genotyping for CYP3A5 indicated that the frequency of CYP3A5^*l/^*3 (heterozygote) and CYP3A5^*3/^*3 (homozygote) were 45% and 50%, respectively. The results indicated these are frequent variants in Japanese. No relationship was observed between docetaxel pharmacokinetics and CYP3A5 genotype in 13 NSCLC patients. The concentration of α 1-acid glycoprotein and the area under the plasma concentration-time curve (AUC) were more important determinants for the efficacy and toxicity of docetaxel.The population pharmacokinetic and pharmacodynamic (PK/PD) analysis has been also performed for S-1, an oral anticancer agent. The plasma concentration of 5-fluorouracil (5-FU) was influenced by the plasma concentration of gimeracil, which is a DPD inhibitor. Renal insufficiency was found to be a risk factor for the toxicity by S-1, because delayed excretion of gimeracil caused higher exposure to 5-FU. Gastrointestinal toxicity (diarrhea) occurred more frequently in Western compared to Japanese patients, and in women compared to men. The present findings will be useful for the safe and optimal dosage of anticancer agents.