# Mechanisms of Altered Hepatic Drug Metabolism and Transport in Pregnancy

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $393,579

## Abstract

ABSTRACT:
Approximately 80% of pregnant women take at least one medication during pregnancy. However, most drugs
prescribed during pregnancy lack dosing information specific to this understudied vulnerable population. This
urgent, unmet public health need results in off-label prescribing, trial-and-error drug dosing, therapeutic failures,
and toxic effects. More precise dosing recommendations are lacking in large part because the key factors that
alter hepatic drug disposition (metabolism and transport) in pregnant women are poorly understood. Drug
metabolizing enzymes (DMEs) and transporters in the liver are integral to the clearance and effects of numerous
drugs used during pregnancy. Consequently, a thorough mechanistic understanding of the key factors that alter
hepatic drug metabolism and transport during pregnancy is essential to more precisely predict in vivo changes
in clearance, optimize drug selection and dosing, and improve maternal and fetal outcomes. Our central
hypothesis is that pregnancy-induced hormonal changes significantly affect maternal drug clearance and
exposure by altering the expression and function of key DMEs and drug transporters in the liver. The overall
objective of this project is to systematically elucidate how, and to what extent, pregnancy hormones alter hepatic
drug metabolism and transport, and the hepatic clearance of clinically relevant drugs used in obstetric patients.
We will test our hypothesis by investigating the effects of pregnancy hormones on the hepatic expression of key
phase I and II DMEs and drug transporters, and the hepatic disposition of established and emerging drugs used
to treat hypertensive disorders of pregnancy (nifedipine, labetalol, pravastatin) and opioid use disorder in
pregnancy (buprenorphine) that exhibit complementary hepatic clearance mechanisms. These effects will be
compared to prototypical probe substrates of key clearance pathways to enable extrapolation of results to
additional drugs. The following specific aims will be accomplished through completion of mechanism-driven
experiments in sandwich-cultured human hepatocytes and humanized mice: (AIM 1) elucidate the effects of
pregnancy hormones on the hepatic expression of key phase I and phase II DMEs, and drug uptake and efflux
transport proteins; (AIM 2) define the impact of pregnancy hormones on the hepatic metabolism of clinically
relevant drugs and probe substrates by key phase I (CYP3A4) and phase II (UGT1A1) DMEs; (AIM 3) evaluate
the impact of pregnancy hormones on the function of key hepatic uptake and efflux transport proteins, and the
hepatobiliary disposition of clinically relevant drugs and probe substrates. This project will provide fundamental
new knowledge on the mechanisms and extent to which pregnancy hormones alter hepatic drug metabolism and
transport, and the hepatic clearance of drugs; establish an experimental platform that elucidates hepatic drug
disposition changes during pregnancy and can be applied s...

## Key facts

- **NIH application ID:** 10380640
- **Project number:** 5R01HD098742-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** CRAIG R LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,579
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380640

## Citation

> US National Institutes of Health, RePORTER application 10380640, Mechanisms of Altered Hepatic Drug Metabolism and Transport in Pregnancy (5R01HD098742-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10380640. Licensed CC0.

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