Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington, USA.
J Clin Pharmacol. 2023 Mar;63(3):363-372. doi: 10.1002/jcph.2169. Epub 2022 Nov 15.
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.
细胞色素 P450 2D6（CYP2D6）在怀孕期间的诱导机制尚未在人类中进行评估。本研究评估了怀孕期间和产后 CYP2D6 和 CYP3A 活性的变化，以及维生素 A 给药对 CYP2D6 活性的影响。47 名 CYP2D6 广泛代谢者（CYP2D6 活性评分为 1 至 2）在 3 个研究窗口（妊娠 25 至 28 周时，研究日 1；妊娠 28 至 32 周时，研究日 2；和产后≥3 个月时，研究日 3）口服右美沙芬（DM）30mg。参与者在研究日 1 后随机分为无补充维生素 A（对照组）或补充维生素 A（每天 10000IU 口服 3 至 4 周）组。使用液相色谱-质谱法从 2 小时后剂量的血浆样本和 4 小时累积尿液样本中测定 DM 及其代谢物右啡烷（DX）和 3-羟吗啡烷（3HM）的浓度。使用 DX/DM 血浆和尿液代谢比值评估 CYP2D6 活性的变化。还使用 3HM/DM 尿液代谢比值评估 CYP3A 活性的变化。与产后相比，妊娠时 DX/DM 尿液比值显著升高（43%）（P=0.03），表明 CYP2D6 活性增加。妊娠时，DX/DM 血浆比值显著升高，活性评分为 1.0（P=0.04），产后则较低。妊娠时 3HM/DM 尿比值显著升高（92%），反映 CYP3A 活性增加（P=0.02）。维生素 A 补充剂并未改变妊娠期间的 CYP2D6 活性；然而，血浆全反式视黄酸（atRA）浓度与妊娠和产后 CYP2D6 活性增加呈正相关。需要进一步研究阐明妊娠期间 CYP2D6 活性增加的机制。
