口服降糖药的遗传药理学研究进展

摘要/Abstract

摘要： 糖尿病是一种受多基因和环境因素共同影响的代谢性疾病。药物代谢酶、受体和转运体的遗传多态性对口服降糖药的体内代谢和降糖疗效有重要作用。本文从细胞色素P450 酶、转运体和受体多态性方面对5 种主要口服降糖药(磺脲类、噻唑烷二酮类、氯茴苯酸类、双胍类、α-葡萄糖甙酶抑制剂)的体内代谢和药物效应的影响作一综述。

关键词: 糖尿病, 药物反应, 基因多态性, CYP450, 受体, 转运体

Abstract: Diabetes mellitus is a metabolic disease influenced by numerous genes and environmental factors. The genetic polymorphisms of drug-metabolizing enzymes, transporters or receptors play very important roles in the metabolism and therapeutical efficacy of oral antidiabetic drugs.In this review, we summarized the effects of genetic polymorphisms of certain CYP450 enzymes, transporters or receptors on the drug metabolism and efficacy of oral antidiabetic drugs including sulfonylureas, thiazolidinediones, meglitinide analogues, biguanides and α-glucosaccharase inhibitors.

Key words: diabetes mellitus, drug response, polymorphism, CYP450, receptor, transporter

中图分类号:

R587.1
R968

张伟, 王安, 周宏灏. 口服降糖药的遗传药理学研究进展[J]. 中国临床药理学与治疗学, 2007, 12(1): 7-10.

ZHANG Wei, WANG An, ZHOU Hong-hao. Progress and research in pharmacogenetics of oral antidiabetic drugs[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(1): 7-10.

参考文献

[1] Roglic G. 糖尿病的流行情况[J]. 国外医学内分泌学分册, 2002;22: 347.
[2] Harrigan RA, NathanMS, Beattie P. Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment[J]. Ann Emerg Med, 2001;38: 68-78.
[3] 周宏灏, 主编. 遗传药理学[M]. 北京: 科学出版社, 2001.
[4] Melander A. Related clinical pharmacology of sulfonylureas[J]. Metabolism, 1987;36: 12-16.
[5] Campbell RK. Related glimepiride: role of a new sulfonylurea in the treatment of type 2 diabetes mellitus[J]. Ann Pharmacother, 1998;32: 1044-1052.
[6] 卢爱华, 舒焱, 周宏灏. 细胞色素氧化酶CYP2C9 的研究进展[J]. 中国临床药理学杂志, 2001;16: 381-385.
[7] Xie HG, Prasad HC, Kim RB, et al. CYP2C9 allelic variants: ethnic distribution and functional significance[J]. Adv Drug Deliv Rev, 2002;18: 1257-1270.
[8] Sullivan-Klose TH, Ghanayem BI, Bell DA, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism[J]. Pharmacogenetics, 1996;6: 341-349.
[9] Bhasker CR, Miners JO, Coulter S, et al. Allelic and functional variability of cytochrome P4502C9[J]. Pharmacogenetics, 1997;7: 51-58.
[10] Inoue K, Yamazaki H, Imiya K, et al. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4'-hydroxylation activities in livers of Japanese and Caucasian populations[J]. Pharmacogenetics, 1997;7: 103-113.
[11] Niemi M, Cascorbi I, Timm R, et al. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes[J]. Clin Pharmacol Ther, 2002;72: 326-332.
[12] Yin OQ, Tomlinson B, Chow MS. CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects[J]. Clin Pharmacol Ther, 2005;78: 370-377.
[13] Kirchheiner J, Bauer S, Meineke I, et al. Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers[J]. Pharmacogenetics, 2002;12: 101-109.
[14] Shon JH, Yoon YR, Kim KA, et al. Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans[J]. Pharmacogenetics, 2002;12: 111-119.
[15] Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes[J]. Diabetes, 1996;45: 1661-1669.
[16] Wagstaff AJ, Goa KL. Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus[J]. Drugs, 2002;62: 1805-1837.
[17] Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone[J]. Br J Clin Pharmacol, 1999;48: 424-432.
[18] Dai D, Zeldin DC, Blaisdell JA, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid[J]. Pharmacogenetics, 2001;11: 597-607.
[19] Dai D, Zeldin DC, Blaisdell JA, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid[J]. Pharmacogenetics, 2001;11: 597-607.
[20] Soyama A, Saito Y, Hanioka N, et al. Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism[J]. Biol Pharm Bull, 2001;24: 1427-1430.
[21] Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily[J]. Br J Clin Pharmacol, 2001;52: 349-355.
[22] Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice[J]. Pharmacol Rev, 2006;58: 521-590.
[23] Kang ES, Park SY, Kim HJ, et al. Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma2 gene on rosiglitazone response in type 2 diabetes[J]. Clin Pharmacol Ther, 2005;78: 202-208.
[24] Yamazaki H, Shibata A, Suzuki M, et al. Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P450 2C8 and P450 3A4 in human liver microsomes[J]. Drug Metab Dispos, 1999;27: 1260-1266.
[25] 王军生, 许振华, 周宏灏. 细胞色素P450 3A4 与药物氧化代谢[J]. 中国临床药理学杂志, 1996;12: 231-235.
[26] Masubuchi Y. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review[J]. Drug Metab Pharmacokinet, 2006;21: 347-356.
[27] Niemi M, Backman JT, Neuvonen M, et al. Rifampin decreases the plasma concentrations and effects of repaglinide[J]. Clin Pharmacol Ther, 2000;68: 495-500.
[28] NiemiM, Backman JT, Kajosaari LI, et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics[J]. Clin Pharmacol Ther, 2005;77: 468-478.
[29] Mikkaichi T, Suzuki T, Tanemoto M, et al. The organic anion transporter (OATP)family[J]. Drug Metab Pharmacokinet, 2004;19: 171-179.
[30] Nishizato Y, Ieiri I, Suzuki H, et al. Polymorphisms of OATPC (SLC21A6)and OAT3 (SLC22A8)genes: consequences for pravastatin pharmacokinetics[J]. Clin Pharmacol Ther, 2003;73: 554-565.
[31] NiemiM, Schaeffeler E, Lang T, et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1)[J]. Pharmacogenetics, 2004;14: 429-440.
[32] Kirchheiner J, Meineke I, Muller G, et al. Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers[J]. J Clin Pharmacokinet, 2004;43: 267-278.
[33] Zhang W, He YJ, Han CT, et al. Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide[J]. Br J Clin Pharmacol, 2006;62: 567-572.
[34] Wang DS, Jonker JW, Kato Y, et al. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin[J]. J Pharmacol Exp Ther, 2002;302: 510-515.
[35] Wang DS, Kusuhara H, Kato Y, et al. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin[J]. Mol Pharmacol, 2003;63: 844-848.