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

为建立抗癌药物最佳给药剂量的药代动力学监测系统，我们首次建立了基于TaqMan PCR等位基因识别技术的细胞色素P450（GYP）2D 6 ^*10、CYP 3A 5 ^*3和CYP 3A 5 ^*6基因多态性快速诊断方法，然后对多西他赛和S-1药代动力学个体差异的影响因素进行了研究。获得所有受试者的书面知情同意书。CYP 2D 6基因分型结果显示，CYP 2D 6 ^*1/^*10（杂合子）和CYP 2D 6 ^*10/^*10（纯合子）的频率分别为43%和23%。CYP 3A 5基因分型结果表明，CYP 3A 5 ^* 1/^*3（杂合子）和CYP 3A 5 ^*3/^*3（纯合子）的频率分别为45%和50%。结果表明，这些是常见的变体在日本。在13例NSCLC患者中未观察到多西他赛药代动力学与CYP 3A 5基因型之间的关系。α 1-酸性糖蛋白的浓度和血浆浓度-时间曲线下面积（AUC）是多西他赛疗效和毒性的重要决定因素，并对口服抗癌药S-1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）的血药浓度受DPD抑制剂吉美拉西的血药浓度影响。发现肾功能不全是S-1毒性的风险因素，因为吉美拉西排泄延迟导致5-FU暴露量增加。胃肠道毒性（腹泻）在西方患者中的发生率高于日本患者，在女性患者中的发生率高于男性患者。本研究结果将有助于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.