人细胞色素P450 2D6多态性及其临床意义:第一部分。
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周科幻
人细胞色素P450 2D6多态性及其临床意义:第一部分。
临床药效学杂志，2009;48(11):689-723。doi: 10.2165 / 11318030-000000000-00000。
- PubMed ID
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19817501 (PubMed视图］
- 摘要
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细胞色素P450 (CYP) 2D6是与遗传多态性相关的研究最多的CYPs之一，但只占所有肝脏CYPs的一小部分(约2-4%)。CYP2D6酶活性存在较大的个体间差异。这种酶在很大程度上是不可诱导的，可以代谢大约25%的现有药物。CYP2D6的典型底物主要是亲脂性碱基，包括一些抗抑郁药、抗精神病药、抗心律失常药、止吐药、β -肾上腺素受体拮抗剂(β -阻滞剂)和阿片类药物。CYP2D6活性在人群中有相当大的范围，包括超快速代谢物(UMs)，广泛代谢物(EMs)，中间代谢物(IMs)和差代谢物(pm)。CYP2D6等位基因分布在不同种族群体中存在相当大的变异性，导致特定人群中pm、im、em和UMs的百分比不同。迄今为止，已经报道了74个CYP2D6基因的等位变异和一系列亚变异，等位基因的数量仍在增加。其中包括全功能等位基因，功能降低的等位基因和零(无功能)等位基因，它们传递了广泛的酶活性，从无活性到底物的超快速代谢。因此，如果使用标准剂量，可能会发生药物不良反应或缺乏药物效果。等位基因*10，*17，*36和*41引起了底物依赖性活性下降。 Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol. The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone is a more potent beta-blocker than its metabolites and the beta-blocking activity during propafenone therapy is more prominent in PMs than EMs, as the parent drug accumulates in PMs. Since flecainide is mainly eliminated through renal excretion, and both R- and S-flecainide possess equivalent potency for sodium channel inhibition, the CYP2D6 phenotype has a minor impact on the response to flecainide. Since the contribution of CYP2D6 is greater for metoprolol than for carvedilol, propranolol and timolol, a stronger gene-dose effect is seen with this beta-blocker, while such an effect is lesser or marginal in other beta-blockers. Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. However, genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships. Further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts of subjects.
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药物 交互 整合药物之间
软件中的交互普罗帕酮 Mirabegron 与米拉贝隆联用可降低普罗帕酮的代谢。
