RT Journal Article
SR Electronic
T1 Effects of Pregnancy on the Pharmacokinetics of Metformin
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.088435
DO 10.1124/dmd.119.088435
A1 Michael Z. Liao
A1 Shannon K. Flood Nichols
A1 Mahmoud Ahmed
A1 Shannon Clark
A1 Gary D. Hankins
A1 Steve Caritis
A1 Raman Venkataramanan
A1 David Haas
A1 Sara K. Quinney
A1 Laura S. Haneline
A1 Alan T. Tita
A1 Tracy Manuck
A1 Joanne Wang
A1 Kenneth E. Thummel
A1 Linda Morris Brown
A1 Zhaoxia Ren
A1 Thomas R Easterling
A1 Mary F. Hebert
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/01/24/dmd.119.088435.abstract
AB This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with GDM vs. non-pregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin mono-therapy (n=24) or in combination with glyburide (n=30) as well as in non-pregnant women with type 2 diabetes mellitus (T2DM, n=24) were determined utilizing non-compartmental analysis. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500 mg and 1000 mg doses, metformin bioavailability, volume of distribution beta (Vβ), 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 (Vβ/F, 33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 mg to 1000 mg orally twice daily significantly increased Vβ/F by 28%, weight adjusted Vβ/F by 32%, 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 following a 500 mg dose of metformin was lower during pregnancy compared to the non-pregnant 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 (GDM) 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 non-linearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance and volume of distribution during pregnancy.