Division of Pharmacology, Department of Internal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
Curr Drug Metab. 2011 Dec;12(10):932-43. doi: 10.2174/138920011798062283.
After the rapid development of new classes of antineoplastic drugs, research activities have focused their efforts to the identification of predictive markers of drug activity and tolerability. Irinotecan (CPT-11) may induce severe toxicities (diarrhea, neutropenia) that limit its clinical use, but the increasing knowledge of its pharmacokinetics offered a potential approach to treatment optimization. Pharmacokinetics, the first area of investigation, has identified markers such as biliary index, the relative extent of conversion and the glucuronidation ratio, which are capable to define the risk for severe adverse effects. Because of the existence of some issues concerning the adoption of pharmacokinetic strategies to optimize CPT-11 dose and schedule, analyses of genetic polymorphisms seemed to offer a more reliable and safer approach for the identification of patients at risk than pharmacokinetics. In this view, the uridine diphosphate glucuronosil transferase isoform 1A1 (UGT1A1) was associated with significant changes in disposition of CPT-11 and its metabolites, and consequently with treatment-induced toxicities. However, the complex pharmacokinetics of irinotecan and the involvement of several enzymes other than UGT (i.e., carboxyl estherases, CYP450 isoforms), and transmembrane transporters (ABCB1, ABCC1, ABCG2, SLCO1B1) make difficult the identification of patients with an optimal sensitivity and specificity, and a large part of variability among patients still remains unexplained. Furthermore, prospective clinical studies that should demonstrate the reliability of those pharmacokinetic and pharmacogenetic markers are still lacking. In the present review, pharmacokinetic and pharmacogenetic markers will be discussed.
随着新型抗肿瘤药物的快速发展，研究活动已将重点放在寻找药物活性和耐受性的预测标志物上。伊立替康（CPT-11）可能会引起严重的毒性（腹泻、中性粒细胞减少症），从而限制其临床应用，但对其药代动力学的深入了解为治疗优化提供了一种潜在的方法。药代动力学是第一个研究领域，它确定了胆汁指数、相对转化程度和葡萄糖醛酸化比值等标志物，这些标志物能够定义发生严重不良反应的风险。由于在采用药代动力学策略来优化 CPT-11 剂量和方案方面存在一些问题，因此分析遗传多态性似乎比药代动力学更能为识别风险患者提供更可靠和更安全的方法。在这种情况下，尿苷二磷酸葡萄糖醛酸转移酶 1A1 同工型（UGT1A1）与 CPT-11 及其代谢物的处置以及由此产生的治疗相关毒性的显著变化有关。然而，伊立替康复杂的药代动力学以及除 UGT（即羧酸酯酶、CYP450 同工型）和跨膜转运蛋白（ABCB1、ABCC1、ABCG2、SLCO1B1）以外的其他几种酶的参与，使得难以确定具有最佳敏感性和特异性的患者，并且患者之间的大部分变异性仍然无法解释。此外，仍然缺乏能够证明这些药代动力学和遗传标记可靠性的前瞻性临床研究。在本综述中，将讨论药代动力学和遗传标记。
