人类细胞色素P450 2 d6多态性及其临床意义:第二部分。
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周科幻
人类细胞色素P450 2 d6多态性及其临床意义:第二部分。
Pharmacokinet。2009; 48 (12): 761 - 804。doi: 10.2165 / 11318070-000000000-00000。
- PubMed ID
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19902987 (在PubMed]
- 文摘
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本文的第一部分讨论了基因突变的潜在功能的重要性和等位基因的人类细胞色素P450 2 d6 CYP2D6基因。间隙的CYP2D6多态性的影响和应对的一系列心血管药物解决。自从CYP2D6的新陈代谢过程中起着重要作用大量的其他药物,本文的第二部分强调了CYP2D6多态性对响应的影响到其他组的临床使用药物。虽然临床研究观察gene-dose效应对于一些三环类抗抑郁药,很难建立清晰的关系他们的药物动力学和药效学参数CYP2D6基因变异;因此,剂量调整基于目前不能推荐CYP2D6表型。有初步证据gene-dose影响常用的选择性5 -羟色胺再摄取抑制剂(SSRIs),但数据对CYP2D6基因型和表型的影响的响应ssri类药物及其不利影响的信息。因此,建议规定ssri类药物剂量的调整基于CYP2D6基因型和表现型可能还不成熟。大量的临床研究表明,有显著的CYP2D6基因型之间的关系和稳态浓度奋乃静,zuclopenthixol,利培酮和氟哌啶醇。然而,发现CYP2D6基因型之间的关系和帕金森症或迟发性运动障碍治疗与传统抗精神病药物是相矛盾的,可能是因为小样本大小,包含与CYP2D6变量新陈代谢,抗精神病药物和co-medication。CYP2D6表现型和基因分型结果似乎是有用的在预测稳态浓度的一些经典抗精神病药物,但其效用在预测必须探索临床疗效。 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.
