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Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of >20% of marketed drugs. CYP2D6 expression and activity exhibit high interindividual variability and is induced during pregnancy. The farnesoid X receptor (FXR) is a transcriptional regulator of CYP2D6 that is activated by bile acids. In pregnancy, elevated plasma bile acid concentrations are associated with maternal and fetal risks. However, modest changes in bile acid concentrations may occur during healthy pregnancy, thereby altering FXR signaling. A previous study demonstrated that hepatic tissue concentrations of bile acids positively correlated with the hepatic mRNA expression of CYP2D6. This study sought to characterize the plasma bile acid metabolome in healthy women ( n = 47) during midpregnancy (25-28 weeks gestation) and ≥3 months postpartum and to determine if plasma bile acids correlate with CYP2D6 activity. It is hypothesized that during pregnancy, plasma bile acids would favor less hydrophobic bile acids (cholic acid vs. chenodeoxycholic acid) and that plasma concentrations of cholic acid and its conjugates would positively correlate with the urinary ratio of dextrorphan/dextromethorphan. At 25-28 weeks gestation, taurine-conjugated bile acids comprised 23% of the quantified serum bile acids compared with 7% ≥3 months postpartum. Taurocholic acid positively associated with the urinary ratio of dextrorphan/dextromethorphan, a biomarker of CYP2D6 activity. Collectively, these results confirm that the bile acid plasma metabolome differs between pregnancy and postpartum and provide evidence that taurocholic acid may impact CYP2D6 activity during pregnancy. SIGNIFICANCE STATEMENT: Bile acid homeostasis is altered in pregnancy, and plasma concentrations of taurocholic acid positively correlate with CYP2D6 activity. Differences between plasma and/or tissue concentrations of farnesoid X receptor ligands such as bile acids may contribute to the high interindividual variability in CYP2D6 expression and activity., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Aims: Pregnancy alters multiple physiological processes including angiogenesis, vasodilation, inflammation, and cellular redox, which are partially modulated by the gasotransmitters hydrogen sulfide (H 2 S) and nitric oxide (NO). In this study, we sought to determine how plasma levels of H 2 S, NO, and the H 2 S-related metabolites thiocyanate (SCN - ), and methanethiol (CH 3 SH) change during pregnancy progression., Materials and Methods: Plasma was collected from 45 women at three points: 25-28 weeks gestation, 28-32 week gestation, and at ≥3 months postpartum. Plasma levels of H 2 S, SCN - , and CH 3 SH were measured following derivatization using monobromobimane followed by LC-MS/MS. Plasma NO was measured indirectly using the Griess reagent., Key Findings: NO and SCN - were significantly lower in women at 25-28 weeks gestation and 28-32 weeks gestation than postpartum while plasma H 2 S levels were significantly lower at 28-32 weeks gestation than postpartum. No significant differences were observed in CH 3 SH., Significance: Previous reports demonstrated that the production of H 2 S and NO are stimulated during pregnancy, but we observed lower levels during pregnancy compared to postpartum. Previous reports on NO have been mixed, but given the related effects of H 2 S and NO, it is expected that their levels would be higher during pregnancy vs. postpartum. Future studies determining the mechanism for decreased H 2 S and NO during pregnancy will elucidate the role of these gasotransmitters during normal and pathological progression of pregnancy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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

Vitamin A is vital to maternal-fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women ( n = 23) during two stages of pregnancy (25-28 weeks gestation and 28-32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25-28 weeks gestation, plasma retinol (-27%), 4-oxo-13- cis -retinoic acid (-34%), and albumin (-22%) concentrations were significantly lower, and all-trans -retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28-32 weeks gestation, plasma retinol (-41%), retinol binding protein 4 (RBP4; -17%), transthyretin (TTR; -21%), albumin (-26%), 13- cis -retinoic acid (-23%) and 4-oxo-13- cis -retinoic acid (-48%) concentrations were significantly lower, whereas plasma all-trans -retinoic acid concentrations (+30%) were significantly higher than ≥3 months postpartum. Collectively, the data demonstrates that in healthy pregnancies, retinol plasma concentrations are lower, but all-trans -retinoic acid concentrations are higher than postpartum.