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.

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

Figures

Figure 1:

(a) Dextrorphan/dextromethorphan ratio in 2-hour plasma sample during pregnancy (study day 1) and postpartum (study day 3). (b) Dextrorphan/dextromethorphan ratio in a cumulative 4-hour urine sample during pregnancy (study day 1) and postpartum (study day 3)​ (c) 3-hydroxy-morphinan/dextromethorphan ratio in a cumulative 4-hour urine sample during pregnancy (study day 1) and postpartum (study day 3). Wilcoxon signed-rank test was used to assess changes between the metabolite to parent plasma and urinary metabolic ratios during and after pregnancy. P

Figure 2:

Dextrorphan/dextromethorphan (DX/DM) 2-hour plasma ratios (a – c) and cumulative 4-hour urinary ratios (d – f) during pregnancy (study day 1) and postpartum (study day 3) in women with CYP2D6 activity scores 1.0 (n = 17), 1.5 (n = 7) and 2.0 (n = 21). Changes in the metabolic ratios during pregnancy and postpartum was evaluated using the Wilcoxon signed-rank test. P

Figure 3:

Effect of vitamin A supplementation on CYP2D6 activity during pregnancy (28 – 32 weeks) in the vitamin A and control groups. (a) Dextrorphan/dextromethorphan (DX/DM) cumulative 4-hour urinary metabolic ratio (b) Dextrorphan/dextromethorphan (DX/DM) 2-hour plasma metabolic ratio (c) 3-hydromorphinan/dextromethorphan (3HM/DM) cumulative 4-hour urinary metabolic ratio. The line in the box represents the median value for each group, and the range of the box depicts the minimum to maximum values. Statistical comparisons of the vitamin A and control group metabolite/parent ratios were made using the Mann Whitney U test with p

Figure 4:

Effect of vitamin A supplementation on CYP2D6 activity during pregnancy (28 – 32 weeks). Dextrorphan/dextromethorphan 2-hour plasma metabolic ratios (a – c) and cumulative 4-hour urinary metabolic ratios (d – f) in CYP2D6 activity scores 1.0 (n = 17), 1.5 (n = 7) and 2.0 (n = 21) are shown. Statistical comparisons of the vitamin A and control group metabolite/parent ratios were made using the Mann Whitney U test with p

Figure 5:

Log transformed urinary DX/DM ratio versus plasma atRA concentrations (nM). Light blue solid dots represent repeated measurement from 47 subjects. Each dark blue solid line represents the prediction from linear mixed effect model for each individual subject. The p-value of the regression coefficient is displayed.