Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
University of Washington, Health Science Building Room H-272M, Box 357610, Seattle, Washington, USA.
AAPS J. 2021 Jan 12;23(1):24. doi: 10.1208/s12248-020-00537-x.
Oxycodone is an opioid analgesic that is commonly prescribed to pregnant women to treat moderate-to-severe pain. It has been shown to cross the placenta and distribute to the fetus. Oxycodone is mainly metabolized by CYP3A4 in the adult liver. Since CYP3A7 is abundantly expressed in the fetal liver and has overlapping substrate specificity with CYP3A4, we hypothesized that the fetal liver may significantly limit fetal exposure to oxycodone. This study showed that oxycodone is metabolized by CYP3A7 to noroxycodone in fetal liver microsomes (FLMs). The measured CYP3A7 expression was 191-409 pmol/mg protein in 14 FLMs, and an intersystem extrapolation factor (ISEF) for CYP3A7 was 0.016-0.066 in the panel of fetal livers using 6β-OH-testosterone formation as the probe reaction. Noroxycodone formation in the fetal liver was predicted from formation rate by recombinant CYP3A7, CYP3A7 expression level and the established ISEF value with average fold error of 1.25. Based on the intrinsic clearance of oxycodone measured in FLM, the fetal hepatic clearance (CL) at term was predicted to be 495 (range: 66.4-936) μL/min, a value that is > 99% lower than the predicted adult liver CL. The predicted fetal hepatic extraction ratio was 0.0019 (range: 0.00003-0.0036). These results suggest that fetal liver metabolism does not quantitatively contribute to the total systemic clearance of oxycodone in pregnant women nor does it provide a barrier for limiting fetal exposure to oxycodone. Additionally, since CYP3A7 forms noroxycodone, an inactive metabolite, the metabolism in the fetal liver is unlikely to affect fetal opioid activity.
羟考酮是一种阿片类镇痛药，常用于治疗孕妇的中重度疼痛。研究表明，羟考酮可穿过胎盘并分布到胎儿体内。羟考酮主要在成人肝脏中经 CYP3A4 代谢。由于 CYP3A7 在胎儿肝脏中大量表达，且与 CYP3A4 具有重叠的底物特异性，我们假设胎儿肝脏可能会显著限制胎儿对羟考酮的暴露。本研究表明，羟考酮在胎儿肝微粒体（FLM）中可被 CYP3A7 代谢为去甲羟考酮。在 14 个 FLM 中，CYP3A7 的测量表达水平为 191-409 pmol/mg 蛋白，在使用 6β-OH-睾酮生成作为探针反应的胎儿肝脏组中，CYP3A7 的内系统外推因子（ISEF）为 0.016-0.066。根据重组 CYP3A7、CYP3A7 表达水平和建立的 ISEF 值预测胎儿肝脏中去甲羟考酮的形成速率，平均误差倍数为 1.25。基于在 FLM 中测量的羟考酮固有清除率，预测足月时胎儿肝脏清除率（CL）为 495（范围：66.4-936）μL/min，该值比预测的成人肝脏 CL 低>99%。预测的胎儿肝脏提取率为 0.0019（范围：0.00003-0.0036）。这些结果表明，胎儿肝脏代谢不会对孕妇体内羟考酮的总全身清除率产生定量贡献，也不会对限制胎儿对羟考酮的暴露产生屏障作用。此外，由于 CYP3A7 形成无活性代谢物去甲羟考酮，因此胎儿肝脏中的代谢不太可能影响胎儿阿片类药物的活性。
