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

为建立确定最佳抗癌药物剂量的药代动力学监测系统，我们首先建立了基于TaqMan PCR等位基因识别法的细胞色素P450 (GYP) 2D6^*10、CYP3A5^*3和CYP3A5^*6等位基因遗传多态性的快速诊断方法，然后研究了造成多西紫杉醇和S-1药代动力学个体差异的因素。收集了93名无血缘关系的志愿者和104名患者的血液样本进行基因分型。获得所有受试者的书面知情同意。CYP2D6基因分型结果显示，CYP2D6^*1/^*10（杂合子）和CYP2D6^*10/^*10（纯合子）的频率分别为43%和23%。CYP3A5基因分型结果显示，CYP3A5^* 1 /^*3（杂合子）和CYP3A5^*3/^*3（纯合子）的频率分别为45%和50%。结果表明，这些变体在日语中很常见。13例NSCLC患者多西他赛药代动力学与CYP3A5基因型无相关性。α 1-酸性糖蛋白浓度和血浆浓度-时间曲线下面积（AUC）是多西紫杉醇疗效和毒性的重要决定因素。口服抗癌药物S-1也进行了群体药代动力学和药效学（PK/PD）分析。5-氟尿嘧啶（5-FU）血药浓度受甲氧嘧啶（一种DPD抑制剂）血药浓度的影响。肾功能不全被发现是S-1毒性的危险因素，因为延迟排泄会导致更多的5-FU暴露。胃肠道毒性（腹泻）在西方患者中比在日本患者中更常见，在女性中比在男性中更常见。本研究结果将有助于确定抗癌药物的安全和最佳剂量。

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.