Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity

Ogochukwu U. Amaeze; Lindsay C. Czuba; Aprajita S. Yadav; Emily E. Fay; Jeffrey LaFrance; Sara Shum; Sue L. Moreni; Jennie Mao; Weize Huang; Nina Isoherranen; Mary F. Hebert

doi:10.1002/jcph.2169

Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity

Ogochukwu U. Amaeze
, Lindsay C. Czuba
, Aprajita S. Yadav
, Emily E. Fay
, Jeffrey LaFrance
, Sara Shum
, Sue L. Moreni
, Jennie Mao
, Weize Huang
, Nina Isoherranen
, Mary F. Hebert

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty-seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3-hydroxymorphinan (3HM), were determined from a 2-hour post-dose plasma sample and cumulative 4-hour urine sample using liquid chromatography–mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P =.03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P =.04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P =.02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all-trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy.

Original language	English
Pages (from-to)	363-372
Number of pages	10
Journal	Journal of Clinical Pharmacology
Volume	63
Issue number	3
DOIs	https://doi.org/10.1002/jcph.2169
State	Published - Mar 2023

Bibliographical note

Publisher Copyright:
© 2022 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Funding

This research was supported by grants from the National Institute of General Medical Sciences (R01GM124264), National Institute on Drug Abuse (P01DA032507), NIH National Center for Advancing Translational Sciences (NCATS) (training grant TL1TR002318), National Institute of General Medical Sciences (training grant T32GM007750), National Institute of Diabetes and Digestive Kidney Diseases (training grant T32DK007247‐42), Bill and Melinda Gates Foundation (INV‐029091), the UW School of Pharmacy's Milo Gibaldi Endowed Chair, and the Elmer M. Plein Endowed Research Fund. The content of this article is solely the authors’ responsibility and does not necessarily represent the official views of the funders. N.I. reports consultancy agreements with Boehringer Ingelheim and Johnson & Johnson, grants from the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) and honoraria from the American Society for Pharmacology and Experimental Therapeutics (ASPET), McGraw Hill, and the American Society for Clinical Pharmacology and Therapeutics (ASCPT). M.H. reports grants or contracts from the NIH National Institute of General Medical Sciences (NIGMS), UC San Diego, and Duke University. E.F. reports grants or contracts from a Dexcom Investigator Initiated Study. W.H. is a stockholder of Roche Holding AG. The other authors declare no conflicts of interest associated with this work.

Funders	Funder number
Boehringer Ingelheim and Johnson & Johnson
National Institutes of Health (NIH)
National Institute on Drug Abuse	P01DA032507
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R01GM124264
National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases	T32DK007247‐42
Bill and Melinda Gates Foundation	INV‐029091
American Society for Pharmacology and Experimental Therapeutics
National Center for Advancing Translational Sciences (NCATS)	T32GM007750, TL1TR002318
Duke-Kunshan University
University of California San Diego Health

Keywords

CYP2D6
CYP3A
dextromethorphan
dextrorphan
postpartum
pregnancy
retinoids
vitamin A

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

Access to Document

10.1002/jcph.2169

Cite this

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title = "Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity",

abstract = "The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty-seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3-hydroxymorphinan (3HM), were determined from a 2-hour post-dose plasma sample and cumulative 4-hour urine sample using liquid chromatography–mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43\%) in pregnancy compared with postpartum (P =.03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P =.04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92\%) during pregnancy, reflecting increased CYP3A activity (P =.02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all-trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy.",

keywords = "CYP2D6, CYP3A, dextromethorphan, dextrorphan, postpartum, pregnancy, retinoids, vitamin A",

author = "Amaeze, \{Ogochukwu U.\} and Czuba, \{Lindsay C.\} and Yadav, \{Aprajita S.\} and Fay, \{Emily E.\} and Jeffrey LaFrance and Sara Shum and Moreni, \{Sue L.\} and Jennie Mao and Weize Huang and Nina Isoherranen and Hebert, \{Mary F.\}",

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AU - Yadav, Aprajita S.

AU - Fay, Emily E.

AU - LaFrance, Jeffrey

AU - Shum, Sara

AU - Moreni, Sue L.

AU - Mao, Jennie

AU - Huang, Weize

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KW - pregnancy

KW - retinoids

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