人细胞色素P450 2D6多态性及其临床意义第二部分。
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周科幻
人细胞色素P450 2D6多态性及其临床意义第二部分。
临床药效学杂志，2009;48(12):761-804。doi: 10.2165 / 11318070-000000000-00000。
- PubMed ID
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19902987 (PubMed视图］
- 摘要
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本文的第一部分讨论了人类细胞色素P450 2D6 (CYP2D6)基因的基因突变和等位基因的潜在功能重要性。研究了CYP2D6多态性对一系列心血管药物的清除和反应的影响。由于CYP2D6在大量其他药物的代谢中起着重要作用，本文的第二部分重点介绍了CYP2D6多态性对其他临床使用药物的反应的影响。虽然临床研究观察到一些三环类抗抑郁药存在基因剂量效应，但很难确定其药代动力学和药效学参数与CYP2D6基因变异之间的明确关系;因此，目前不建议根据CYP2D6表型调整剂量。有初步证据表明，基因剂量对常用的选择性血清素再摄取抑制剂(SSRIs)有影响，但CYP2D6基因型/表型对SSRIs反应及其不良反应的影响的数据很少。因此，基于CYP2D6基因型/表型的处方SSRIs剂量调整建议可能还不成熟。多项临床研究表明，CYP2D6基因型与奋那静、zuclopenthixol、利培酮、氟哌啶醇的稳态浓度存在显著相关性。然而，关于CYP2D6基因型与帕金森病或使用传统抗精神病药物治疗迟发性运动障碍之间的关系的研究结果是相互矛盾的，可能是因为样本量小，包括具有不同CYP2D6代谢的抗精神病药物，以及联合用药。CYP2D6表型和基因分型似乎在预测一些经典抗精神病药物的稳态浓度方面有用，但它们在预测临床效果方面的有用性必须加以探索。 Therapeutic drug monitoring has been strongly recommended for many antipsychotics, including haloperidol, chlorpromazine, fluphenazine, perphenazine, risperidone and thioridazine, which are all metabolized by CYP2D6. It is possible to merge therapeutic drug monitoring and pharmacogenetic testing for CYP2D6 into clinical practice. There is a clear gene-dose effect on the formation of O-demethylated metabolites from multiple opioids, but the clinical significance of this may be minimal, as the analgesic effect is not altered in poor metabolizers (PMs). Genetically caused inactivity of CYP2D6 renders codeine ineffective owing to lack of morphine formation, decreases the efficacy of tramadol owing to reduced formation of the active O-desmethyl-tramadol and reduces the clearance of methadone. Genetically precipitated drug interactions might render a standard opioid dose toxic. Because of the important role of CYP2D6 in tamoxifen metabolism and activation, PMs are likely to exhibit therapeutic failure, and ultrarapid metabolizers (UMs) are likely to experience adverse effects and toxicities. There is a clear gene-concentration effect for the formation of endoxifen and 4-OH-tamoxifen. Tamoxifen-treated cancer patients carrying CYP2D6*4, *5, *10, or *41 associated with significantly decreased formation of antiestrogenic metabolites had significantly more recurrences of breast cancer and shorter relapse-free periods. Many studies have identified the genetic CYP2D6 status as an independent predictor of the outcome of tamoxifen treatment in women with breast cancer, but others have not observed this relationship. Thus, more favourable tamoxifen treatment seems to be feasible through a priori genetic assessment of CYP2D6, and proper dose adjustment may be needed when the CYP2D6 genotype is determined in a patient. Dolasetron, ondansetron and tropisetron, all in part metabolized by CYP2D6, are less effective in UMs than in other patients. Overall, there is a strong gene-concentration relationship only for tropisetron. CYP2D6 genotype screening prior to antiemetic treatment may allow for modification of antiemetic dosing. An alternative is to use a serotonin agent that is metabolized independently of CYP2D6, such as granisetron, which would obviate the need for genotyping and may lead to an improved drug response. To date, the functional impact of most CYP2D6 alleles has not been systematically assessed for most clinically important drugs that are mainly metabolized by CYP2D6, though some initial evidence has been identified for a very limited number of drugs. The majority of reported in vivo pharmacogenetic data on CYP2D6 are from single-dose and steady-state pharmacokinetic studies of a small number of drugs. Pharmacodynamic data on CYP2D6 polymorphisms are scanty for most drug studies. Given that 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.
