Department of Pharmacology & Toxicology, St Vincents Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
Clin Pharmacokinet. 2011 Feb;50(2):81-98. doi: 10.2165/11534750-000000000-00000.
Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin. Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.
二甲双胍被广泛用于治疗 2 型糖尿病。它是一种双胍类药物，由法国紫丁香（Galega officinalis）中的胍衍生物格尔丁（galegine）开发而成。在化学上，它是一种亲水性碱，在生理 pH 值下以阳离子形式存在（>99.9%）。因此，其通过细胞膜的被动扩散应该非常有限。二甲双胍的平均口服生物利用度（F）为 55±16%。它主要从小肠吸收。二甲双胍以原形从尿液中排泄。肾功能良好的患者多次给药后，二甲双胍的消除半衰期（t(½)）约为 5 小时。根据已发表的二甲双胍药代动力学数据，计算了其清除率的人群平均值。健康受试者和肾功能良好的糖尿病患者的人群平均肾清除率（CL(R)）和口服后表观总清除率（CL/F）分别估计为 510±130 mL/min 和 1140±330 mL/min。在肾功能范围内，二甲双胍的人群平均 CL(R)和 CL/F 值分别是肌酐清除率（CL(CR)）的 4.3±1.5 和 10.7±3.5 倍。由于 CL(R)和 CL/F 与 CL(CR)成比例下降，因此肾功能受损的患者应根据 CL(CR)的降低按比例减少二甲双胍的剂量。二甲双胍的口服吸收、肝脏摄取和肾脏排泄主要由有机阳离子转运体（OCTs）介导。OCT1 的内含子变异（单核苷酸多态性 [SNP] rs622342）与杂合子对血糖的影响降低以及二甲双胍对血浆葡萄糖的影响在纯合子中缺失有关。多药和毒素外排转运蛋白 [MATE1]（G>A，SNP rs2289669）的内含子变异也与二甲双胍的抗高血糖作用略有增加有关。总体而言，OCTs 和其他阳离子转运体结构变异对二甲双胍药代动力学的影响很小，对临床反应的后续影响也有限。然而，OCT1 和 OCT3 在肝脏中的表达水平在个体间差异很大，可能对二甲双胍的肝脏摄取和临床疗效的变化贡献更大。乳酸酸中毒是双胍类药物的可怕不良反应，但在接受二甲双胍治疗的患者中，其发生率非常低。我们建议，在给药间隔内将二甲双胍的平均血浆浓度保持在 2.5 mg/L 以下，以将这种不良反应的发生风险降至最低。
