Pharmacokinetics of metformin during pregnancy

Abstract

Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 +/- 243 ml/min, P < 0.01) and late pregnancy (625 +/- 130 ml/min, P < 0.01) compared with postpartum (477 +/- 132 ml/min). These changes reflected significant increases in creatinine clearance (240 +/- 70 ml/min, P < 0.01 and 207 +/- 56 ml/min, P < 0.05 versus 165 +/- 44 ml/min) and in metformin net secretion clearance (480 +/- 190 ml/min, P < 0.01 and 419 +/- 78 ml/min, P < 0.01 versus 313 +/- 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (<5 ng/ml) and 1263 ng/ml. The daily infant intake of metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was <0.5% of the mother's weight-adjusted dose. Our results indicate that metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

Fig. 1.

LC-MS chromatograms of metformin, including a blank sample (A), a blank sample spiked with 100 ng of metformin (B), and a sample obtained at 3 h postdose from a patient in late gestation treated with 850 mg of metformin every 8 h (C).

Fig. 2.

Metformin secretion clearance (A), renal clearance (B), and apparent oral clearance (C) during mid (T2) and late pregnancy (T3) and postpartum (PP). White, gray, and black symbols indicate G/G (wild type), G/T, and T/T SLC22A2 genotypes at loci G808T, respectively.

Fig. 3.

Correlation between metformin renal clearance and creatinine clearance (A) or metformin net secretion clearance (B) for a total of 35 subjects (over 62 study days) during pregnancy and postpartum. White, gray, and black symbols indicate G/G, G/T, and T/T SLC22A2 genotypes at loci G808T, respectively.

Fig. 4.

Plasma concentrations (means ± S.D.) versus time profile during early, mid, and late pregnancy as well as postpartum in women treated with 500 mg of metformin twice daily.

Fig. 5.

Correlation between metformin apparent oral clearance and creatinine clearance (A) or metformin net secretion clearance (B) for a total of 14 subjects (over 24 study days), taking 500 mg of metformin twice daily, during pregnancy and postpartum. White and gray symbols indicate G/G and G/T SLC22A2 genotypes at loci G808T, respectively.

Fig. 6.

Metformin concentration in maternal plasma and breast milk of a representative subject over one dosing interval at steady state. The subject was treated with 1500 mg of metformin once daily for type 2 diabetes.