Carrier-mediated transport of metformin across the human placenta determined by using the ex vivo perfusion of the placental cotyledon model.
OBJECTIVE
Metformin is a polar positively charged compound. The aim of the study was to characterize its permeability across the human placenta using the ex vivo placental perfusion model.


METHODS
Selected cotyledons from term placentas were cannulated and dually perfused. Metformin (10 mg/L, 1000 mg/L) and a permeability reference, antipyrine (50 mg/L), were added to the maternal circulation. Samples from maternal and fetal compartments were analyzed for metformin and antipyrine by high performance liquid chromatography (HPLC). The permeation of metformin was also studied using the parallel artificial membrane permeation assay (PAMPA) that was designed to predict passive transcellular permeability of drugs.


RESULTS
In this study, 15 complete placental perfusion experimental set-ups were performed. The mean percent transport increased as metformin concentrations were raised and it was 11 +/- 1.32 and 16.92 +/- 0.98 for 10 mg/L and 1000 mg/L, respectively. The transport rate of metformin across the placenta was asymmetric yet, an active efflux against the gradient concentration could not be observed. Using the PAMPA assay, we confirmed that metformin does not cross by passive diffusion.


CONCLUSIONS
The data suggest that metformin permeability across the placenta is mediated by a carrier that transport cationic compounds bi-directionally, with a higher transfer rate from the fetal to the maternal side.
Department of Obstetrics & Gynecology, The E. Wolfson Medical Center, Holon, and Sackler School of Medicine, Tel Aviv University, Israel.
Michal
M
Kovo
Naomi
N
Kogman
Oded
O
Ovadia
Ishak
I
Nakash
Abraham
A
Golan
Amnon
A
Hoffman
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D000983:Antipyrine / Q000493:pharmacokinetics; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008431:Maternal-Fetal Exchange; D008687:Metformin / Q000493:pharmacokinetics*; D008954:Models, Biological; D010920:Placenta / Q000098:blood supply / Q000378:metabolism*; D021041:Placental Circulation; D011247:Pregnancy
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D008687:Metformin; D000983:Antipyrine