Sambol N C, Chiang J, Lin E T, Goodman A M, Liu C Y, Benet L Z, Cogan M G
Department of Pharmacy, University of California San Francisco 94143-0446, USA.
J Clin Pharmacol. 1995 Nov;35(11):1094-102. doi: 10.1002/j.1552-4604.1995.tb04033.x.
The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle-age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850-mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high-performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35-40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74-78% lower than in the healthy young/middle-age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23-33% lower than in the young/middle-age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CLcr; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = alpha + beta.CLcr + gamma.CL*cr.age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non-insulin-dependent diabetes) population.
评估了肾功能损害和年龄对二甲双胍药代动力学的影响。研究对象包括6名年轻、12名老年和3名中年健康成年人，以及15名患有不同程度慢性肾功能损害（CRI）的成年人，分别给予单次850毫克盐酸二甲双胍片。采集多个全血、血浆和尿液样本，采用高效液相色谱（HPLC）法分析二甲双胍水平。在健康老年个体中，二甲双胍的血浆和全血清除率/绝对生物利用度值[CL/F和(CL/F)b]以及相应的肾清除率值（CLR和CLR,b）比健康年轻个体的相应值低35 - 40%。这两组在分布容积（Vd）、达峰时间（tmax）以及与二甲双胍在尿液中出现相关的参数方面无显著差异。在中度和重度CRI组中，所有清除率值比健康年轻/中年组低74 - 78%，且该组所有其他可评估的药代动力学参数（tmax除外）均有显著差异。在轻度CRI组中，二甲双胍清除率值比年轻/中年组低23 - 33%，是唯一有显著差异的参数。基于合并数据的回归分析，肌酐清除率（CLcr；校正体表面积）和年龄均为二甲双胍清除率的预测因子，以下模型最符合数据：CL/F [或(CL/F)b、CLR、CLR,b] = α + β.CLcr + γ.CL*cr.年龄。中度和重度CRI患者或轻度但肾功能并非绝对稳定患者不应使用二甲双胍。老年患者和稳定轻度CRI患者的初始剂量和最大剂量应降至一般人群（即无非胰岛素依赖型糖尿病患者）给药剂量的约三分之一。
