Foley Kevin F, Quigley Denise I
Kaiser Permanente NW, Portland, OR, USA.
MLO Med Lab Obs. 2010 Jan;42(1):32-4.
The ultimate goal in measuring CYP2D6 (or any other CYP450) function or identifying variant alleles is to predict effective therapeutic doses and responses in patients. This is the promise of individualized medicine. By knowing a patient's disposition to drugs, he could be started on appropriate dosing regimens without the extensive trial-and-error period that is common with psychiatric medications. We could also avoid drugs whose metabolism may prove to be problematic, choosing second-line therapies which are metabolized by different, unaffected enzymes. Of course, knowing a genotype is not very useful unless we couple the genotype findings with clinically validated dosing algorithms. Dosing recommendations for PM, EM, IM, and UM patients are beginning to appear in the literature for various classes of drugs but, at present, there are no well-accepted guidelines available. The Food and Drug Administration does encourage the incorporation of pharmacogenomic testing for investigational compounds in the development process. As the notion of PGx becomes more familiar and more clinical trials are completed, evidence-based dosing adjustments should be forthcoming. Although the biochemistry and pharmacology of CYP450 drug metabolism has made huge strides, the application of pharmacogenomics has not yet become commonplace for a number of reasons. Drug metabolism is a complex process, and CYP2D6 may not be the only polymorphic protein involved in a given drug's metabolism. Also, both primary and secondary metabolic pathways exist for drugs, the latter of which may be utilized when other drugs or endogenous compounds occupy the principle pathway. Given the possibility of multiple metabolic pathways, the presence of co-medications, inducers, and inhibitors in the diet and disease changes, predicting drug metabolism in a person remains difficult even when a given CYP450 genotype is obtained. Also there are multiple variants which can be present and consideration must be given as to which variant allele(s) to look for while, at the same time, always considering the cost/benefit ratio of a possible testing algorithm. Despite the numerous uncontrolled variables involved in drug metabolism and the inability for pharmacogenomics to address them all, there remains some promise for CYP2D6 genotyping to at least help physicians hone in on appropriate dose ranges before therapy is initiated or in identifying individuals at metabolic extremes who are at the highest risk for adverse outcomes. Ultimately, if CYP2D6 characterization is shown to be an evidence-based improvement in the practice of psychiatric medicine, laboratorians will need to be prepared for an influx of requests for these tests.
测量CYP2D6（或任何其他CYP450）功能或鉴定变异等位基因的最终目标是预测患者的有效治疗剂量和反应。这就是个性化医疗的前景。通过了解患者对药物的处置情况，可在没有精神科药物常见的广泛试错期的情况下，为患者开始使用适当的给药方案。我们还可以避免使用那些代谢可能存在问题的药物，选择由不同的、未受影响的酶代谢的二线治疗药物。当然，除非我们将基因型检测结果与经过临床验证的给药算法相结合，否则了解基因型并没有太大用处。针对各种药物类别，文献中已开始出现针对PM、EM、IM和UM患者的给药建议，但目前尚无被广泛接受的指南。美国食品药品监督管理局确实鼓励在研发过程中将药物基因组学检测纳入研究性化合物中。随着药物基因组学的概念变得更加为人熟知，并且更多的临床试验完成，基于证据的剂量调整应该会随之而来。尽管CYP450药物代谢的生物化学和药理学已经取得了巨大进展，但由于多种原因，药物基因组学的应用尚未变得普遍。药物代谢是一个复杂的过程，并且CYP2D6可能不是参与特定药物代谢的唯一多态性蛋白。此外，药物存在一级和二级代谢途径，当其他药物或内源性化合物占据主要途径时，可能会利用后者。鉴于存在多种代谢途径、饮食中合并用药、诱导剂和抑制剂以及疾病变化，即使获得了特定的CYP450基因型，预测个体的药物代谢仍然很困难。此外，可能存在多种变异，必须考虑寻找哪些变异等位基因，同时始终考虑可能的检测算法的成本效益比。尽管药物代谢涉及众多无法控制的变量，并且药物基因组学无法解决所有这些变量，但CYP2D6基因分型至少在帮助医生在开始治疗前确定合适的剂量范围或识别代谢极端的个体（这些个体发生不良后果的风险最高）方面仍有一些前景。最终，如果CYP2D6特征被证明是精神医学实践中基于证据的改进，那么检验人员将需要为这些检测请求的大量涌入做好准备。
