KIDNEY-FUNCTION AND AGE ARE BOTH PREDICTORS OF PHARMACOKINETICS OF METFORMIN

The effects of renal impairment and age on the pharmacokinetics of met formin were evaluated. The subjects, including 6 young, 12 elderly, an d 3 middle-age healthy adults and 15 adults with various degrees of ch ronic renal impairment (CRI) each were given a single, 850-mg metformi n HCl tablet. Multiple whole blood, plasma, and urine samples were col lected and analyzed for metformin levels using a high-performance liqu id chromatography (HPLC) method. In healthy elderly individuals, the p lasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)(b)], and corresponding renal clearance values (CL(R) and CL (R,b)) of metformin were 35-40% lower than the respective values in he althy young individuals. These two groups did not differ significantly with respect to volume of distribution (V-d), time to peak concentrat ion (t(max)), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values wer e 74-78% lower than in the healthy young/middle-age group, and all oth er evaluable pharmacokinetic parameters (with the exception of t(max)) differed significantly in this group. In the mild CRI group, clearanc e values of metformin, which were 23-33% lower than in the young/middl e-age group, were the only parameters that differed significantly. Bas ed on a regression analysis of the combined data, both creatinine clea rance (CL(cr); corrected for body surface area) and age are predictor s of metformin clearance, with the following model best fitting the da ta: CL/F [or (CL/F)(b), CL(R), CL(R,b)] = alpha + beta . CL(cr) + gam ma . CL(cr) . age. Metformin should not be used in patients with mode rate and severe CRI, or in patients with mild, but not absolutely stab le, renal impairment. The initial and maximum doses in elderly patient s and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non-insul in-dependent diabetes) population.