# Effects of Retinoids on CYP2D6 Activity and Variability in Special Populations

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $549,949

## Abstract

PROJECT SUMMARY
CYP2D6, a key drug-metabolizing enzyme, is involved in the metabolism of ~20% of all drugs. We
hypothesize that natural variation in retinoic acid concentrations and retinoid signaling in the liver
regulate CYP2D6 expression and activity in humans, which in turn contributes to CYP2D6
pharmacokinetic variability and CYP2D6 induction during pregnancy. We will take a mechanistic
approach and test the relationship between retinoid concentrations and CYP2D6 activity in 2 studies evaluating
from the perspective of CYP2D6 induction during pregnancy, repression of induction with vitamin A
administration and repression of normal CYP2D6 activity with 13-cis-retinoic acid (isotretinoin) in non-
pregnant adolescent patients. Pregnant and adolescent patients often require treatment for chronic
conditions, which can include CYP2D6 substrates. After accounting for genetic variation, there is still a great
deal of unaccounted variability in CYP2D6 activity in these special populations making clinical management
challenging. Basic science studies suggest that retinoids play an important role in CYP2D6 regulation. Our
objective is to understand the role of retinoids in CYP2D6 activity in pregnant, postpartum and adolescent
patients and translate new laboratory findings into humans. Our Specific Aims are:
Specific Aim 1. To determine if vitamin A administration decreases CYP2D6 activity during pregnancy.
In this aim, we will evaluate the effect of vitamin A administration on pregnancy-induced CYP2D6 activity. This
study will provide mechanistic understanding of CYP2D6 induction and variability during pregnancy as well as
provide a potential clinical strategy for management of pregnant women that require CYP2D6 substrates.
Specific Aim 2. To investigate if isotretinoin (13-cis-retinoic acid) administration decreases CYP2D6
activity in adolescent patients. In this aim, we will conduct a drug-drug interaction study evaluating the
effects of 13-cis-retinoic acid on non-induced CYP2D6 activity in adolescent patients. Secondary analysis will
evaluate the relationship between retinoid concentrations and CYP2D6 activity in these special populations. In
both Specific Aims we will utilize dextromethorphan as our CYP2D6 probe substrate. Through these
complementary aims, we will be the first to conduct mechanistic testing of endogenous regulation of CYP2D6
activity in humans. The results could overcome a critical barrier to safe and effective administration of CYP2D6
substrates in adolescent and pregnant patients. Based on our compelling preliminary data, we expect to
identify a novel mechanism of CYP2D6 regulation in humans and a potential management strategy for
CYP2D6 induction and variability during pregnancy, with the intention of improving safety and efficacy of
medications for these vulnerable patients. This work is critical for the provision of individualized therapy and
along with genetics, the first step in development of an endogenous biomarker for C...

## Key facts

- **NIH application ID:** 9904729
- **Project number:** 5R01GM124264-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** MARY F HEBERT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $549,949
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904729

## Citation

> US National Institutes of Health, RePORTER application 9904729, Effects of Retinoids on CYP2D6 Activity and Variability in Special Populations (5R01GM124264-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904729. Licensed CC0.

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