The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c
The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c
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DOI：
10.1097/fpc.0b013e32834c0010
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发表时间：
2011-12-01
影响因子：
2.6
通讯作者：
Brosen, Kim
中科院分区：
文献类型：
--
作者：
Christensen, Mette M. H.;Brasch-Andersen, Charlotte;Brosen, Kim
目的探讨OCT 1、OCT 2、MATE 1、MATE 2和PMAT基因变异对二甲双胍和糖化血红蛋白（Hb 1Ac）稳态血浆谷浓度的影响。方法南丹麦糖尿病研究是一项2 × 2 × 2析因、前瞻性、随机、双盲、安慰剂对照、多中心研究。159例患者接受1 g二甲双胍，每日两次，连续治疗，并在治疗3、6和9个月后获得415次重复血浆二甲双胍测量结果。（范围，54-4133 ng/ml，rho = 0.55），并与OCT 1中功能降低的等位基因数量相关（无、1个或2个：642、542、397 ng/ml; P = 0.001）。最初和长期Hb 1Ac的绝对下降也与OCT 1中功能降低的等位基因的数量相关，导致二甲双胍在6和24 months.Conclusion后的药效学作用减弱，在2型糖尿病患者的大队列中，我们首次证实或显示：（a）谷稳态二甲双胍血浆浓度的巨大80倍变异性，（B）OCT 1活性影响二甲双胍稳态药代动力学，和（c）OCT 1基因型与二甲双胍治疗期间的HbA 1c有关。药理遗传学和基因组学21：837-850（C）2011年沃尔特斯·克鲁沃健康垂直栏Lippincott威廉姆斯&威尔金斯。
Objective The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac).Method The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment.Results The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54-4133 ng/ml, rho = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months.Conclusion In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous 80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment. Pharmacogenetics and Genomics 21:837-850 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.