Understanding Pregnancy-induced Changes in the Disposition of Norbuprenorphine, Metformin and Glyburide in Mice and Humans for Optimizing Drug Therapy during Pregnancy

Abstract

Pharmacotherapy usage during pregnancy is common and increasing. In the current clinical practice, healthcare providers are increasingly prescribing buprenorphine (BUP) for opioid addiction treatment, as well as metformin, and glyburide for gestation diabetes mellitus (GDM). Due to the dual risks and benefits to the mother and fetus, it is important to understand how pregnancy affects the disposition of these drugs and their metabolites. To understand the effects of P-gp and Bcrp on tissue distribution during pregnancy, and the effects of pregnancy on drug disposition, we administered norbuprenorphine (NBUP), the major active metabolite of BUP, to nonpregnant wild-type (WT), pregnant WT, pregnant P-gp (Mdr1a/1b) knockout (KO), and pregnant P-gp/Bcrp (Mdr1a/1b/Abcg2) KO mice. We have shown that that fetal exposure to NBUP and norbuprenorphine-3-β-D-glucuronide (NBUP-G) in pregnant mice accounts for ~60% and ~700% of maternal plasma exposure, respectively, suggesting that fetal exposure to the two major active metabolites of BUP is substantial and hence caution should be taken regarding fetal safety with the use of BUP during pregnancy. We have also demonstrated significant differential impact of P-gp on fetal and brain exposure to NBUP, with a much greater role of P-gp in restricting NBUP distribution across the blood brain barrier (BBB) versus the blood placental barrier (BPB). Subsequently, we demonstrated that the systemic clearance (CL) of NBUP in WT pregnant mice was ~2.5-fold higher compared with WT non-pregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ~2-times greater than non-pregnant mice. Targeted LC-MS/MS proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased (~50%) in pregnant mice versus non-pregnant mice. Recently, metformin and glyburide have gained increasing popularity for the GDM management. However, the optimal dosing regimens for these two drugs during pregnancy are unknown. We conducted a multicenter, prospective Phase II, randomized, parallel-design pharmacokinetics study. We analyzed the pharmacokinetics of orally administered steady-state metformin in pregnant women with GDM and non-pregnant women with Type-2-Diabetes Mellitus (T2DM), and the pharmacokinetics of oral glyburide in fed and fasted pregnant subjects with GDM. For the metformin cohort, with both 500 mg and 1000 mg doses, bioavailability, volume of distribution, clearance and renal clearance of metformin were increased during pregnancy. For the glyburide cohort, simultaneous consumption of a standardized meal increased glyburide dose-normalized AUC and decreased glyburide apparent oral volume of distribution β, apparent oral clearance, and half-life. Overall, this body of information provides insights pharmacokinetic and mechanistic understanding of the use of buprenorphine, metformin, and glyburide during pregnancy, laying the foundation to optimize management of opiate addiction and gestational diabetes mellitus during pregnancy.