Robert F, Fendri S, Hary L, Lacroix C, Andréjak M, Lalau J D
Service d'Endocrinologie-Nutrition, Hôpital Sud, Amiens, France.
Diabetes Metab. 2003 Jun;29(3):279-83. doi: 10.1016/s1262-3636(07)70037-x.
Although the existence of a deep compartment for metformin has long been hypothesized, there is still little direct information concerning metformin distribution in individual tissues in man. The only available study involves chronic metformin therapy. In that study, the measurement of metformin in erythrocytes provided a reliable indicator of metformin distribution and of potential accumulation. To determine the kinetics of metformin in plasma and in erythrocytes after acute oral administration, we performed the present study in healthy subjects after a single oral dose of metformin and compared the pharmacokinetics parameters in erythrocytes to those in plasma.
Six nondiabetic participants took the study dose of 850 mg metformin at 8: 00 AM after a non-standardized breakfast (i.e., as recommended in clinical practice). Blood samples were collected for metformin measurement in plasma and in erythrocytes at 0, 1, 2, 3, 4, 6, 9, 24, 33, 48, 57, and 72 h.
Maximum metformin concentration was attained at 3.0 +/- 0.3 h in plasma and 4.7 +/- 0.5 h in erythrocytes. This difference was not significant. Metformin concentrations peaked at a maximum almost 6 times higher in plasma than in erythrocytes (1.7 +/- 0.1 and 0.3 +/- 0.0 mg/l, respectively). However, because the elimination half-life of metformin was much longer in erythrocytes (23.4 +/- 1.9 h vs. 2.7 +/- 1.2 h), there was no difference in area under the curve between plasma and erythrocytes. The distribution volume (plasma) was calculated to be 146 +/- 11 l. Plasma and erythrocytes concentration-time curves showed that metformin was not detectable in plasma 24 hours after the oral administration, while it remained detectable in erythrocytes up to 48 hours. Metformin concentrations crossed approximately 13 hours after having reached their maximum values in plasma, approximately 16 h after metformin intake.
Having demonstrated the rapid elimination of metformin from plasma and its slow disappearance from erythrocytes, the presents results should contribute to adjustment of metformin dosage to renal function, assessment of drug compliance, and retrospective analysis (when blood samples are drawn with delay) of the link between metformin and development of lactic acidosis. Most importantly, the present findings should help to ascertain the optimal dosage of metformin, particularly in elderly patients.
尽管长期以来一直假设二甲双胍存在一个深部分布室，但关于二甲双胍在人体各组织中的分布仍缺乏直接信息。唯一可用的研究涉及慢性二甲双胍治疗。在该研究中，红细胞中二甲双胍的测量提供了二甲双胍分布和潜在蓄积的可靠指标。为了确定急性口服给药后二甲双胍在血浆和红细胞中的动力学，我们在健康受试者单次口服二甲双胍后进行了本研究，并比较了红细胞和血浆中的药代动力学参数。
6名非糖尿病参与者在非标准化早餐（即临床实践中推荐的早餐）后于上午8:00服用850mg二甲双胍的研究剂量。在0、1、2、3、4、6、9、24、33、48、57和72小时采集血样，用于测量血浆和红细胞中的二甲双胍。
血浆中二甲双胍浓度在3.0±0.3小时达到最大值，红细胞中在4.7±0.5小时达到最大值。这种差异不显著。血浆中二甲双胍浓度峰值几乎比红细胞中高6倍（分别为1.7±0.1和0.3±0.0mg/l）。然而，由于二甲双胍在红细胞中的消除半衰期长得多（23.4±1.9小时对2.7±1.2小时），血浆和红细胞曲线下面积没有差异。计算出分布容积（血浆）为146±11l。血浆和红细胞浓度-时间曲线显示，口服给药后24小时血浆中检测不到二甲双胍，而红细胞中直到48小时仍可检测到。二甲双胍浓度在血浆中达到最大值后约13小时交叉，二甲双胍摄入后约16小时交叉。
本研究结果表明二甲双胍从血浆中快速消除，从红细胞中缓慢消失，这有助于根据肾功能调整二甲双胍剂量、评估药物依从性以及对二甲双胍与乳酸性酸中毒发生之间的联系进行回顾性分析（当血样采集延迟时）。最重要的是，本研究结果应有助于确定二甲双胍的最佳剂量，尤其是在老年患者中。
