Gestational age‐dependent maternal‐fetal glyburide disposition in pregnant mice (1141.5)

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Glyburide (Gly) is routinely used to treat hyperglycemia during pregnancy. Our objective was to determine if maternal‐fetal disposition of Gly and metabolites is dependent on gestational age in pregnant mice because similar studies cannot be done in humans. Following retro‐orbital injection of Gly, maternal plasma and fetuses were collected at 0.5‐240 min after dosing. Pharmacokinetic parameters were determined using a pseudo‐profile based bootstrap approach and compartmental/noncompartmental analyses. Maternal Gly clearance increased 2‐fold on gestation day (gd) 15 and 19 versus gd 0. Gly depletion analysis using mouse liver microsomes confirmed that gestational age‐dependent changes in Gly clearance is caused by increases in hepatic metabolism. Maternal metabolite/Gly area under the curve (AUC) ratios were low throughout gestation (~0.004), indicating an increase in both metabolite formation and clearance. Fetal/maternal Gly AUC ratios doubled from gd 15 to 19 (0.02 to 0.04), which is likely due to decreased expression of placental efflux transporter Bcrp1 on gd 19 versus 15. Our data suggest that clinical dosages of Gly may need to be doubled to treat hyperglycemia in pregnant women compared to nonpregnant women.Grant Funding Source: Supported by the NICHD [U10HD047892], NCATS [TL1 RR025016], and NIH [T32 GM 007750]