Gestational diabetes mellitus is a major complication of human pregnancy. The oral clearance (CL) of glyburide, an oral anti-diabetic drug, increases 2-fold in pregnant women during late gestation versus non-pregnant controls. In this study, we examined gestational age-dependent changes in maternal-fetal pharmacokinetics (PK) of glyburide and metabolites in a pregnant mouse model. Non-pregnant and pregnant FVB mice were given glyburide by retro-orbital injection. Maternal plasma was collected over 240 min on gestation days (gd) 0, 7.5, 10, 15 and 19; fetuses were colleceted on gd 15 and 19. Glyburide and metabolites were quantified using HPLC-MS, and PK analyses were performed using a pooled data bootstrap approach. Maternal CL of glyburide increased ≈2-fold on gd 10, 15, and 19 compared to non-pregnant controls. CLint of glyburide in maternal liver microsomes also increased as gestation progressed. Maternal metabolite/glyburide AUC ratios were generally unchanged or slightly decreased throughout gestation. Total fetal exposure to glyburide was < 5% of maternal plasma exposure, and was doubled on gd 19 versus gd 15. Fetal metabolite concentrations were below the limit of assay detection. This is the first evidence of gestational age-dependent changes in glyburide PK. Increased maternal glyburide clearance during gestation is attributable to increased hepatic metabolism. Metabolite elimination may also increase during pregnancy. In the mouse model, fetal exposure to glyburide is gestational age-dependent and low compared to maternal plasma exposure. These results indicate that maternal glyburide therapeutic strategies may require adjustments in a gestational-age dependent manner if these same changes occur in humans.
- The American Society for Pharmacology and Experimental Therapeutics