Gardiner Sharon J, Begg Evan J
Department of Medicine, Christchurch School of Medicine, Private Bag 4345, Christchurch, New Zealand.
Pharmacol Rev. 2006 Sep;58(3):521-90. doi: 10.1124/pr.58.3.6.
The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
药物遗传学在个体化治疗方面具有广阔前景。然而，尽管有诸多宣称，但目前它在临床实践中的应用却很少。主要问题在于，支持治疗前基因检测的证据基础薄弱。代谢存在遗传变异性的药物的药理学往往很复杂。很少有药物具有简单或单一的消除途径。有些药物具有活性代谢物或对映体，它们具有不同的活性和消除途径。只有当作用部位所有活性部分的总摩尔活性可预测地受到基因型或表型影响时，药物剂量才可能受到影响。药物浓度的变化必须足够显著，以在正常变化之上提供“信号”，并且必须存在真正的浓度 - 效应关系。药物的治疗指数也会影响检测的实用性。在考虑所有这些因素后，需要权衡前瞻性检测的益处与成本以及其他效应终点。很少有药物满足这些要求也就不足为奇了。有合理证据支持基因分型或表型分析的药物（和酶）包括琥珀胆碱/米库氯铵（丁酰胆碱酯酶）以及硫唑嘌呤/6 - 巯基嘌呤（硫嘌呤甲基转移酶）。有潜在理由进行前瞻性检测的药物包括华法林（CYP2C9）、哌克昔林（CYP2D6），或许还有质子泵抑制剂（CYP2C19）。目前没有其他药物有足够的证据支持进行前瞻性检测，尽管有些值得进一步评估。在本综述中，我们总结了目前与药物代谢酶相关的药物遗传学证据基础。
