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Applications of CYP450 Testing in the Clinical Setting

机译:CYP450检测在临床中的应用

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摘要

Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25 % of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homozygous and heterozygous carriers of CYP2C9 variant alleles require lower doses of phenytoin to reach therapeutic plasma concentrations, and are at increased risk of toxicity. New diagnostic techniques made safer and easier should allow quicker diagnosis of metabolic variations. Genotyping and phenotyping may therefore be considered where dosing guidelines according to CYP genotype have been published, and help identify the right molecule for the right patient.
机译:药物反应的个体差异是一个主要的临床问题。调节药物代谢酶活性的多药和遗传多态性(细胞色素P450,CYP)被确定为药物反应变异性的来源。我们在此提供有关主要CYP多态性(CYP2D6,CYP2C19和CYP2C9)对药物治疗的临床影响的相关数据,其中可以考虑基因分型和表型分型,并在可用时制定了指南。 CYP2D6负责高达25%的常用处方药物的氧化代谢,例如抗抑郁药,抗精神病药,阿片类药物,抗心律失常药和他莫昔芬。超快速代谢者(UM)表型被认为是抗抑郁药治疗无效的原因,而据报导,不良代谢者(PMs)与几种精神药物(地昔帕明,文拉法辛,阿米替林,氟哌啶醇)发生毒性的风险增加。 CYP2D6多态性影响对前药阿片类药物(可待因,曲马多和羟考酮)的镇痛反应。在CYP2D6的PMs中,已观察到镇痛作用降低,而在UMs中,曲马多和可待因的报告有危及生命的毒性。 CYP2D6 PM表型与美托洛尔,噻吗洛尔,卡维地洛和普罗帕酮的毒性风险增加相关。尽管关于CYP2D6基因型与他莫昔芬作用之间的相关性有相互矛盾的报道,但CYP2D6基因型可能在绝经后妇女选择激素辅助治疗中有用。 CYP2C19负责代谢氯吡格雷,质子泵抑制剂(PPI)和某些抗抑郁药。 CYP2C19变异等位基因的载体显示产生氯吡格雷活性代谢产物的能力降低,并且出现不良心血管事件的风险增加。对于PPIs,已表明在CYP2C19变异等位基因的携带者中,平均胃内pH值和幽门螺杆菌根除率更高。 CYP2C19参与几种抗抑郁药的代谢。由于CYP2C19 PM中不良反应的风险增加,因此建议减少某些药物(丙咪嗪,舍曲林)的剂量。 CYP2C9负责代谢维生素K拮抗剂(VKA),非甾体抗炎药(NSAID),磺酰脲类,血管紧张素II受体拮抗剂和苯妥英钠。对于VKA,CYP2C9基因多态性与较低剂量,达到治疗稳定性的时间更长以及超治疗国际标准化比率(INR)的频率有关。可以使用处方算法以使剂量适应基因型。尽管现有数据存在争议,但一些研究表明CYP2C9变异等位基因携带者发生NSAID相关胃肠道出血的风险增加。还观察到CYP2C9多态性与磺酰脲类和血管紧张素II受体拮抗剂的药代动力学之间的关系。然而,对低血糖和血压的临床影响是中等的。最后,CYP2C9变异等位基因的纯合子和杂合子携带者需要较低剂量的苯妥英钠才能达到治疗性血浆浓度,并且具有增加的毒性风险。新的诊断技术变得更安全,更容易,应该可以更快地诊断代谢变化。因此,在根据CYP基因型的剂量指导原则已经发布的情况下,可以考虑基因分型和表型分析,并有助于为合适的患者识别合适的分子。

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