The Impact of Pregnancy on Antihypertensive Drug Metabolism and Pharmacokinetics: Current Status and Future Directions

ABSTRACT

Introduction

Hypertensive disorders of pregnancy (HDP) are rising in prevalence, and increase risk of adverse maternal and fetal outcomes. Physiologic changes occur during pregnancy that alter drug pharmacokinetics. However, antihypertensive drugs lack pregnancy-specific dosing recommendations due to critical knowledge gaps surrounding the extent of gestational changes in antihypertensive drug pharmacokinetics and underlying mechanisms.

Areas covered

This review (1) summarizes currently recommended medications and dosing strategies for non-emergent HDP treatment, (2) reviews and synthesizes existing literature identified via a comprehensive PubMed search evaluating gestational changes in the maternal pharmacokinetics of commonly prescribed HDP drugs (notably labetalol and nifedipine), and (3) offers insight into the metabolism and clearance mechanisms underlying altered HDP drug pharmacokinetics during pregnancy. Remaining knowledge gaps and future research directions are summarized.

Expert Opinion

A series of small pharmacokinetic studies illustrate higher oral clearance of labetalol and nifedipine during pregnancy. Pharmacokinetic modeling and preclinical studies suggest these effects are likely due to pregnancy-associated increases in hepatic UGT1A1- and CYP3A4-mediated first-pass metabolism and lower bioavailability. Accordingly, higher and/or more frequent doses may be needed to lower blood pressure during pregnancy. Future research is needed to address various evidence gaps and inform the development of more precise antihypertensive drug dosing strategies.

KEYWORDS:

• Hypertension
• hypertensive disorders of pregnancy
• labetalol
• oral antihypertensives
• nifedipine
• pharmacokinetics
• pregnancy

Article highlights

• Hypertensive disorders of pregnancy (HDP) increase risk for adverse maternal and fetal outcomes, and frequently require use of antihypertensive medications (most notably labetalol and nifedipine).

• Physiologic and molecular changes occur during pregnancy that can alter maternal drug disposition and pharmacokinetics through various mechanisms.

• Pregnancy-related hormones increase UGT1A1 and CYP3A4 expression in human hepatocytes, which are primarily responsible for the hepatic metabolism and clearance of labetalol and nifedipine, respectively.

• Multiple studies have demonstrated higher oral clearance and lower plasma concentrations of labetalol and nifedipine following oral administration during pregnancy.

• These changes are most likely mediated by increased maternal hepatic UGT1A1- and CYP3A4-mediated metabolism, and decreased bioavailability secondary to enhanced first-pass metabolism.

• Pregnancy-related decreases in plasma labetalol and nifedipine concentrations following oral administration suggest the need for increased and/or more frequent dosing.

• A better understanding of the extent and mechanisms underlying antihypertensive pharmacokinetic changes during pregnancy will create opportunities for more precise medication selection and dosing in HDP patients.

Declaration of interest

The author(s) have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This publication was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH/NICHD) grant [R01 HD098742] to CR Lee. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.