The AmpliChip™ CYP450 Genotyping Test -: Integrating a new clinical tool
The AmpliChip™ CYP450 Genotyping Test -: Integrating a new clinical tool
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DOI：
10.1007/bf03256453
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Murray-Carmichael, Elaina
中科院分区：
文献类型：
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作者：
de Leon, Jose;Susce, Margaret T.;Murray-Carmichael, Elaina
AmpliChip（TM）CYP 450检测分析患者细胞色素P450（CYP 2D 6）和CYP 2C 19基因型，是将个性化处方引入临床环境的重要一步。对药物不良反应（ADR）、遗传革命和药物遗传学的兴趣也随着这一工具的引入而汇聚在一起，预计这将是未来5-10年内新一轮此类工具的第一个。AmpliChip（TM）CYP 450检测是基于微阵列技术，该技术结合了玻璃微阵列上精确位置的杂交和荧光标记系统。它将个体分为两种CYP 2C 19表型（快代谢者[EM]和慢代谢者[PM]），并分为四种CYP 2D 6表型CYP 2D 6是一种代谢酶，具有四种活性水平，（或表型）：具有异常高活性的UM;正常受试者，称为EM;具有低活性的IM;和无CYP 2D 6活性的PM（高加索人7%，其他种族1-3%）。CYP 2D 6 PM和ADR之间相关性的证据水平相对合理，包括对一些典型抗精神病药和三环类抗抑郁药（TCA）病例对照研究的系统评价。其他表型的证据相当有限。CYP 2D 6 PM表型可能与利培酮ADR和因ADR而停药相关。文拉法辛、阿立哌唑、度洛西汀和托莫西汀是通过CYP 2D 6代谢的新药，但需要对CYP 2D 6基因型的临床相关性进行研究。CYP 2D 6代谢的非精神病药物包括美托洛尔、他莫昔芬和可待因类药物。CYP 2C 19 PM（3-4%的白人和非洲裔美国人，14-21%的亚洲人）可能需要调整某些TCA、吗氯贝胺和西酞普兰的剂量。药物遗传学的未来取决于克服严重障碍的能力，包括在资助机构、制药公司和一些科学评论家的抵抗下进行和发表研究的困难。假设有更多的研究发表，药物遗传学的临床应用可能会受到经济因素和缺乏医生教育的影响。美国FDA批准的测试，如AmpliChip（TM）CYP 450测试，和FDA定义的CYP 2D 6作为“有效的生物标志物”的组合使得CYP 2D 6基因分型成为临床环境中第一个成功的药物遗传学测试的主要候选者。人们可以使用微阵列技术来测试数百种单核苷酸多态性（SNP），但是考虑到单基因方法如CYP 2D 6的困难，非常复杂的药物遗传学方法不太可能在未来5-10年内进入临床市场。
The AmpliChip(TM) CYP450 Test, which analyzes patient genotypes for cytochrome P450 (CYP) genes CYP2D6 and CYP2C19, is a major step toward introducing personalized prescribing into the clinical environment. Interest in adverse drug reactions (ADRs), the genetic revolution, and pharmacogenetics have converged with the introduction of this too], which is anticipated to be the first of a new wave of such tools to follow over the next 5-10 years. The AmpliChip(TM) CYP450 Test is based on microarray technology, which combines hybridization in precise locations on a glass microarray and a fluorescent labeling system. It classifies individuals into two CYP2C19 phenotypes (extensive metabolizers [EMs] and poor metabolizers [PMs]) by testing three alleles, and into four CYP2D6 phenotypes (ultrarapid metabolizers [UMs], EMs, intermediate metabolizers [IMs], and PMs) by testing 27 alleles, including seven duplications.CYP2D6 is a metabolic enzyme with four activity levels (or phenotypes): UMs with unusually high activity; normal subjects, known as EMs; IMs with low activity; and PMs with no CYP2D6 activity (7% of Caucasians and 1-3% in other ethnic groups). Levels of evidence for the association between CYP2D6 PMs and ADRs are relatively reasonable and include systematic reviews of case-control studies of some typical antipsychotics and tricyclic antidepressants (TCAs). Evidence for other phenotypes is considerably more limited. The CYP2D6 PM phenotype may be associated with risperidone ADRs and discontinuation due to ADRs. Venlafaxine, aripiprazole, duloxetine, and atomoxetine are newer drugs metabolized by CYP2D6 but studies of the clinical relevance of CYP2D6 genotypes are needed. Non-psychiatric drugs metabolized by CYP2D6 include metoprolol, tamoxifen, and codeine-like drugs.CYP2C19 PMs (3-4% of Caucasians and African Americans, and 14-21% of Asians) may require dose adjustment for some TCAs, moclobemide, and citalopram. Other drugs metabolized by CYP2C19 are diazepam and omeprazole.The future of pharmacogenetics depends on the ability to overcome serious obstacles, including the difficulties of conducting and publishing studies in light of resistance from grant agencies, pharmaceutical companies, and some scientific reviewers. Assuming more studies are published, pharmacogenetic clinical applications may be compromised by economic factors and the lack of physician education. The combination of a US FDA-approved test, such as the AmpliChip(TM) CYP450 Test, and an FDA definition of CYP2D6 as a 'valid biomarker' makes CYP2D6 genotyping a prime candidate to be the first successful pharmacogenetic test in the clinical environment. One can use microarray technology to test for hundreds of single nucleotide polymorphisms (SNPs) but, taking into account the difficulties for single gene approaches such as CYP2D6, it is unlikely that very complex pharmacogenetic approaches will reach the clinical market in the next 5-10 years.