EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela University, Bergondo, Coruña, Spain.
Neurodegener Dis. 2010;7(1-3):167-9. doi: 10.1159/000289230. Epub 2010 Mar 3.
The application of genomic procedures as diagnostic and therapeutic tools is a major challenge for the coming decades. Pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. About 25% of the 100 most prescribed drugs in the USA and the EU are psychotropic drugs, currently used in dementia. Approximately 60-80% of CNS drugs are metabolized via enzymes of the CYP gene superfamily; 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 57.76% of patients with Alzheimer's disease are extensive metabolisers (EMs) for CYP2D6 enzymes, 31.06% are intermediate metabolisers (IMs), 5.28% are poor metabolisers (PMs), and 5.90% are ultrarapid metabolisers (UMs); 73.71% are CYP2C19-EMs, 25.12% IMs, and 1.16% PMs; 60.87% are CYP2C9-EMs, 34.16% IMs, and 4.97% PMs; 82.75% are CYP3A4/5-EMs, 15.88% IMs, and 1.37% UMs. A trigenic cluster integrating CYP2D6+CYP2C19+CYP2C9 polymorphic variants yields 82 different haplotype-like profiles, representing 36 different pharmacogenetic phenotypes in which only 26.51% of patients show a pure 3EM phenotype. These data clearly indicate that the incorporation of pharmacogenomic protocols to dementia research and clinical trials can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improve drug efficacy and safety.
基因组程序作为诊断和治疗工具的应用是未来几十年的主要挑战。药物基因组因素可能占药物处置和药效学中药物变异性的 60-90%。美国和欧盟最常开的 100 种药物中约有 25%是精神药物，目前用于痴呆症。大约 60-80%的中枢神经系统药物通过 CYP 基因超家族的酶代谢；18%的神经安定药是 CYP1A2 酶的主要底物，40%是 CYP2D6，23%是 CYP3A4；24%的抗抑郁药是 CYP1A2 酶的主要底物，5%是 CYP2B6，38%是 CYP2C19，85%是 CYP2D6，38%是 CYP3A4；7%的苯二氮䓬类药物是 CYP2C19 酶的主要底物，20%是 CYP2D6，95%是 CYP3A4。大约 57.76%的阿尔茨海默病患者是 CYP2D6 酶的广泛代谢者（EMs），31.06%是中间代谢者（IMs），5.28%是弱代谢者（PMs），5.90%是超快代谢者（UMs）；73.71%是 CYP2C19-EMs，25.12%是 IMs，1.16%是 PMs；60.87%是 CYP2C9-EMs，34.16%是 IMs，4.97%是 PMs；82.75%是 CYP3A4/5-EMs，15.88%是 IMs，1.37%是 UMs。一个整合 CYP2D6+CYP2C19+CYP2C9 多态性变异的三基因簇产生 82 种不同的类似单倍型的表型，代表 36 种不同的药物遗传学表型，其中只有 26.51%的患者表现出纯 3EM 表型。这些数据清楚地表明，将药物基因组学方案纳入痴呆症研究和临床试验可以通过帮助开发具有成本效益的药物来促进治疗优化，并提高药物的疗效和安全性。
