Effects of Pregnancy on the Pharmacokinetics of Metformin

Abstract

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V _β ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V _β /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V _β /F by 28%, weight-adjusted V _β /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.

Fig. 1.

Mean (error bar S.D.) steady-state metformin (500 mg orally twice daily) in pregnant women with gestation diabetes mellitus (n = 39) and nonpregnant women with type 2 diabetes mellitus (n = 9). Circles indicate concentrations in women with gestational diabetes mellitus, and squares indicate concentrations in women with type 2 diabetes mellitus.

Fig. 2.

Mean (error bar S.D.) steady-state metformin concentration-time curves for pregnant women receiving 500 mg orally twice daily (n = 39) and 1000 mg orally twice daily (n = 15). Circles indicate concentration with the 500 mg cohort, and squares indicate concentration with the 1000 mg cohort.

Fig. 3.

(A) Correlation between creatinine clearance and metformin renal clearance in pregnant women with GDM (solid circles) and nonpregnant women with T2DM (solid triangles) taking metformin 500 and 1000 mg orally twice daily. (B). Correlation between metformin renal clearance and renal secretion clearance in pregnant women with GDM (solid circles) and nonpregnant women with T2DM (solid triangles) taking metformin 500 and 1000 mg orally twice daily (n = 68).

Fig. 4.

Ratios of umbilical cord arterial and venous plasma concentrations to maternal concentrations as a function of duration between the last maternal metformin dose and the time of sample collection. Solid circles represent metformin umbilical cord arterial: maternal plasma concentration ratios. Solid triangles represent metformin umbilical cord venous: maternal plasma concentration ratios.