Rochat Bertrand
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Clin Pharmacokinet. 2005;44(4):349-66. doi: 10.2165/00003088-200544040-00002.
Although activity of cytochrome P450 isoenzymes (CYPs) plays a major role in the fate of anticancer agents in patients, there are relatively few clinical studies that evaluate drug metabolism with therapeutic outcome. Nevertheless, many clinical reports in various non-oncology fields have shown the dramatic importance of CYP activity in therapeutic efficacy, safety and interindividual variability of drug pharmacokinetics. Moreover, variability of drug metabolism in the liver as well as in cancer cells must also be considered as a potential factor mediating cancer resistance. This review underlines the role of drug metabolism mediated by CYPs in pharmacokinetic variability, drug resistance and safety. As examples, biotransformation pathways of tamoxifen, paclitaxel and imatinib are reviewed. This review emphasises the key role of therapeutic drug monitoring as a complementary tool of investigation to in vitro data. For instance, pharmacokinetic data of anticancer agents have not often been published within subpopulations of patients who show ultra-rapid, extensive or poor metabolism (e.g. due to CYP2D6 and CYP2C19 genotypes). Besides kinetic variability in the systemic circulation, induction of CYP activity may participate in creating drug resistance by speeding up the cancer agent degradation specifically in the target cells. For one cancer agent, various mechanisms of resistance are usually identified within different cell clones. This review also tries to emphasise that drug resistance mediated by CYP activity in cancer cells should be taken into consideration to a greater degree. The unequivocal identification of the metabolising enzymes involved in clinical conditions will eventually allow improvement and individualisation of anticancer agent therapy, i.e. drug dosage and selection. In addition, a more complete understanding of the metabolism of anticancer agents will assist in the prediction of drug-drug interactions, as anticancer agent combinations are becoming more prevalent.
尽管细胞色素P450同工酶（CYPs）的活性在患者体内抗癌药物的转归中起主要作用，但评估药物代谢与治疗效果的临床研究相对较少。然而，各个非肿瘤领域的许多临床报告表明，CYPs活性在治疗效果、安全性及药物药代动力学的个体间差异方面具有极其重要的意义。此外，肝脏以及癌细胞中药物代谢的变异性也必须被视为介导癌症耐药性的一个潜在因素。本综述强调了CYPs介导的药物代谢在药代动力学变异性、耐药性及安全性方面的作用。作为示例，对他莫昔芬、紫杉醇和伊马替尼的生物转化途径进行了综述。本综述强调了治疗药物监测作为体外数据补充研究工具的关键作用。例如，抗癌药物的药代动力学数据在显示超快、广泛或代谢不良（如由于CYP2D6和CYP2C19基因型）的患者亚群中并不常被公布。除了体循环中的动力学变异性外，CYPs活性的诱导可能通过加速靶细胞中抗癌药物的降解而参与产生耐药性。对于一种抗癌药物，通常在不同的细胞克隆中可鉴定出多种耐药机制。本综述还试图强调，应更大程度地考虑癌细胞中由CYPs活性介导的耐药性。明确鉴定临床情况下涉及的代谢酶最终将有助于改善抗癌药物治疗并实现个体化，即药物剂量和选择。此外，随着抗癌药物联合使用越来越普遍，更全面地了解抗癌药物的代谢将有助于预测药物相互作用。
