Shah Rashmi R, Smith Robert L
Rashmi Shah Consultancy Ltd, Gerrards Cross, UK.
Br J Clin Pharmacol. 2015 Feb;79(2):222-40. doi: 10.1111/bcp.12441.
Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion.
表型转化是一种将药物的基因型广泛代谢者（EMs）转化为表型慢代谢者（PMs）的现象，从而将其临床反应改变为基因型PMs的临床反应。表型转化通常由非遗传外在因素引起，对以基因型为重点的临床结局关联研究的分析和解释以及常规临床实践中的个性化治疗具有重大影响。由于基因型EM人群中经常发生表型转化，导致高表型变异性或基因型-表型不匹配，这意味着表型PM受试者的实际数量可能大于仅根据其基因型预测的数量，因为许多基因型EM在表型上是PM。如果基因型-表型不匹配的表型转化人群（对CYP2D6研究最为广泛）如证据所示那么庞大，那么以基因型为重点的关联研究（通常仅将基因型与临床结局相关联）就存在真正的风险，可能会错过临床上强大的药物遗传学关联，从而损害推进个性化医疗前景的任何潜力。本综述主要关注联合用药引起的表型转化，并讨论纠正当前一些不足的潜在方法。它提倡在以基因型为重点的关联研究中对受试者进行常规表型分析，并提出一种新的命名法来对研究人群进行分类。即使有强有力且可靠的数据将患者的基因型与临床结局相关联，但由于潜在的基因型-表型不匹配，在将这些知识应用于常规药物治疗时仍存在临床问题。常规临床实践中的药物诱导表型转化仍然是一个重大的公共卫生问题。因此，个性化医疗面临的需要解决的主要挑战包括识别以下因素：（i）易发生表型转化的药物；（ii）可导致表型转化的联合用药；以及（iii）表型转化期间及之后需要应用的剂量调整。
