Of Mice and Women: Understanding Pregnancy-Induced Changes in Glyburide PK/PD for the Improved Management of Gestational Diabetes Mellitus (GDM)

Abstract

Pregnancy-induced changes in drug PK is explained by changes in physiology and expression of metabolic enzymes and transporters. We determined mRNA expression of enzymes and transporters in the maternal liver, kidney, small intestine, and placenta of pregnant mice by microarray analysis. A full summary of gene expression changes is listed in Supplemental Tables 1-14. Glyburide is commonly prescribed to treat gestational diabetes mellitus, a major complication of pregnancy. Gestational age-dependent changes in glyburide PK have not been characterized. We examined pregnancy-induced changes in the maternal-fetal disposition of glyburide and its primary metabolites using a pregnant mouse model, and found maternal CL, V_&beta, and V_ss approximately doubled by mid-late gestation. Glyburide depletion rate in mouse liver microsomes increased as gestation progressed, suggesting increased CL is related to increased hepatic metabolism. Fetal exposure to glyburide was low, but doubled from mid to late pregnancy. Fetal exposure/metabolism of glyburide is also not well characterized. We determined the kinetic parameters of CYP3A enzymes for glyburide depletion; characterized glyburide metabolism by human fetal livers; and identified the enzyme responsible. M5 was the predominant metabolite generated by fetal CYP3A7 and human fetal liver microsomes (HFLMs). CYP3A7 protein levels in HFLMs were highly correlated with glyburide Clint, 16&alpha-OH DHEA formation, and 4′-OH MDZ formation. CYP3A5 and CYP3A7 genotype, fetal sex, gestational age, and post-mortem interval did not alter CYP3A7 protein expression or glyburide Clint. In recent years, oral hypoglycemic agents such as glyburide and metformin have gained increasing popularity for the treatment of GDM. Data is quite limited regarding the PD of glyburide and metformin during pregnancy. We completed an interim analysis of glyburide monotherapy, metformin monotherapy, or glyburide/metformin combination therapy in women with gestational diabetes compared to healthy pregnant women and non-pregnant women with type-2 diabetes mellitus receiving metformin. Pharmacodynamic analyses of blood glucose, insulin, and C-peptide data were performed, and estimates of insulin sensitivity, beta-cell responsivity, and disposition index (DI) were compared across treatment groups. The full study is still ongoing. Overall, this body of research provides novel insight for the optimization of oral hypoglycemic therapies in the management of gestational diabetes mellitus.