临床个体化用药中的药物基因组学考虑

摘要/Abstract

摘要： 虽然引起药物反应个体差异的原因很多, 但遗传因素起相当重要的作用。药物代谢酶、转运药物的蛋白质、受体和其它药物靶体的遗传多态性与药物效应、毒性的个体差异密切相关。药物基因组学是利用已知的基因组学理论, 研究遗传因素对药物反应的影响, 即研究药物动力学和药效学差异的基因特征, 以及基因变异所致的不同个体对药物的不同反应。深入研究遗传因素与临床合理用药之间的重要关系, 确定引起个体对药物处置和疗效差异的遗传学特征, 将为个体化合理用药提供强有力的科学依据。本文简要介绍药物在血浆中结合的蛋白质的基因多态性和与高血压相关的药物基因组学在临床个体化合理用药中的意义。

关键词: 药物基因组学, 遗传多态性, 个体差异, 个体化用药

Abstract: Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications.Pharmacogenomics is to study of how genes affect the individual response to drugs.There are some evidences that in the future the use of pharmacogenomics could help to enhance the effects of drugs and reduce the adverse drug reactions (ADRs), as it aims to predict which patients are likely to respond to a particular drug and which patients are likely to have significant ADRs.Pharmacogenomics studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby providing a strong scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution.In this article some examples of genetic polymorphisms which affecting drug pharmacokinetics (in protein binding of drugs in plasma) and pharmacodynamics (correlated with antihypertensive drugs) are briefly illustrated.

Key words: pharmacogenomics, genetic polymorphism, individual difference, individualized therapy

中图分类号:

R968

李金恒. 临床个体化用药中的药物基因组学考虑[J]. 中国临床药理学与治疗学, 2007, 12(4): 361-365.

LI Jin-heng. Consideration of pharmacogenomics in individualized therapy on clinical practice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(4): 361-365.

参考文献

1 Sadee W.Genomics and drugs:Finding the optimal drug for the right patient[J].Pharm Res, 1998;15:959-963.
2 李金恒.基因多态性与临床个体化用药[J].医学研究生学报, 2005;18:769-772.
3 Evans WE, Relling MV.Pharmacogenomics:translating functional genomics into rational therapeutics[J].Science, 1999; 286:487-491.
4 Severino G, Del-Zompo M.Adverse drug reactions:role of pharmacogenomics[J].Pharmacol Res, 2004;49:363-373.
5 Bartfai T.Pharmacogenomics in drug development:societal and technical aspects[J].Pharmacogenomics J, 2004;4:226-232.
6 Siest G, Jeannesson E, Berrahmoune H, et al.Pharmacogenomics and drug response in cardiovascular disorders[J]. Pharmacogenomics, 2004;5:779-802.
7 Romkes M, Buch SC.Genotyping technologies:application to biotransformation enzyme genetic polymorphism screening[J]. MethodsMol Biol, 2005;291:399-414.
8 Li JH, Lu AY.Role of pharmacokinetics and metabolism in drug discovery and development[J].Pharmacol Rev, 1997;49: 403-449.
9 Grace AA, Camm AJ.Quinidine[J].N Engl J Med, 1998; 338:35-45.
10 Woo E, Greenblatt DJ.Pharmacokinetic and clinical implications of quinidine protein binding[J].J Pharmaceut Sci, 1979; 68:466-470.
11 Li JH, Pan H, Wu ZP, et al.Determination of free digoxin in sera of 8 patients with chronic cardiac insufficiency[J].Acta Pharmacol Sin, 1995;16:47-50.
12 Son DS, Hariya S, Shimoda M, et al.Contribution of ;α1-acid glycoprotein to plasma protein binding of some basic antimicrobials in pigs[J].J Vet Pharmacol Ther, 1996;19:176-183.
13 Routledge PA.The plasma protein binding of basic drugs[J]. Br J Clin Pharmacol, 1986;22:499-506.
14 Li JH, Xu JQ, LI Y, et al.Genetic polymorphisms of orosomucoid on the Han population in Nanjing of Cnina[J].Clin Chim Acta, 1999;288:161-168.
15 Li JH, Xu JQ, Cao XM, et al.Influence of the ORM1 phenotypes on serum unbound concentration and protein binding of quinidine[J].Clin Chim Acta, 2002;317:85-92.
16 Kishino S, Nomura A, Zhai SD, et al.Changes in the binding capacity of alpha-1-acid gly coprotein in patients with renal insufficiency[J].Ther Drug Monit, 1995;17:449-453.
17 Johnson JA, Turner ST.Hypertension pharmacogenomics:current status and future directions[J].Curr Opin Mol Ther, 2005;7:218-225.
18 Trotta R, DonatiMB, Iacoviello L.Trends in pharmacogenomics of drug acting on hypertension[J].Pharmacol Res, 2004; 49:351-356.
19 王瑞石, 胡伟新, 李瑛.高血压病的药物基因组学研究[J].肾脏病与透析肾移植杂志, 2003;12:262-267.
20 Bloem LJ, Manatunga A, Tewksbury DA, et al.The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children[J].J Clin Invest, 1995; 95:948.
21 Brand E, Chatelain N, Paillard F, et al.Detection of putative functional angiotensinogen(AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis[J]. Eur J Human Genet, 2002;10:715-723.
22 Sugiyama T, Morita H, Kato N, et al.Lack of sex-specific effects on the association between angiotensin-converting enzyme gene polymorphism and hypertension in Japanese[J].Hypertes Res, 1999;22:55-59.
23 Casari G, Barlassina C, Cusi D, et al.Association of the alpha-adducin locus with essential hypertension[J].Hypertension, 1995;25:320-326.
24 Cusi D, Barlassina C, Azzani T, et al.Polymorphisms of ;α-adducin and salt sensitivity in patients with essential hypertension[J].Lancet, 1997;349:1353-1357.
25 Glorioso N, Manunta P, Filigheddu F, et al.The role of alpha-adducin polymorphism in blood pressure and sodium handing regulation may not be excluded by a negative association study[J].Hypertension, 1999;34:649-654.
26 Kato N, Sugiyama T.Lack of association between the alpha-adducin locus and essential hypertension in Japanese population [J].Hypertension, 1998;31:730-733.
27 侯嵘, 刘治全, 薛明战, 等.;α-内收蛋白Gly460Trp 变异与中国汉族人原发性高血压的相关性研究[J].中华医学遗传学杂志, 2000;17:413-416.
28 Hingorani AD, Jia H, Stevens PA, et al.Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition[J].J Hypertens, 1995;13:1602-1609.
29 Stavroulakis GA, Makris TK, Krespi PG, et al.Predicting response to chronic antihypertensive treatment with fosinopril:the role of angiotensin-converting enzyme gene polymorphism[J]. Cardiovasc Drugs Ther, 2000;14:427-432.
30 O' toole L, Stewart M, Padfield P, et al.Effect of the insertion deletion polymorphism of the angiotensin-converting enzyme gene on response to angiotensin-converting enzyme inhibitors in patients with heart failure[J].J Cardiovasc Pharmacol, 1998; 32:988-994.
31 Ueda S, Meredith PA, Morton JJ, et al.ACE (I D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug(enalaprilat) in humans[J].Circulation, 1998;98:2148-2153.
32 Poch E, Gonzalez D, Giner V, et al.Molecular basis of salt sensitivity in human hypertension[J].Hypertension, 2001;38: 1204-1209.
33 Sciarrone MT, Stella P, Barlassina C, et al.ACE and alphaadducin polymorphism as markers of individual response to diuretic therapy[J].Hypertension, 2003;41:398-403.
34 Psaty BM, Smith NL, Heckbert SR, et al.Diuretic therapy, the ;α-adducin gene variant, and the risk of myocardial infarction of stroke in persons with treated hypertension[J].JAMA, 2002;287:1680-1689.

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