Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (H.M.W., J.N.L.); and Biomolecular Sciences Institute & Department of Chemistry & Biochemistry, School of Integrated Science & Humanity, College of Arts, Sciences, & Education, Florida International University, Miami, Florida (J.C.H.).
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (H.M.W., J.N.L.); and Biomolecular Sciences Institute & Department of Chemistry & Biochemistry, School of Integrated Science & Humanity, College of Arts, Sciences, & Education, Florida International University, Miami, Florida (J.C.H.)
Drug Metab Dispos. 2024 May 16;52(6):516-525. doi: 10.1124/dmd.123.001434.
The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by cytochrome P450 3A7 (CYP3A7) in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development. Of the 13 HCV antivirals we investigated, 8 (∼62%) inhibited CYP3A7 metabolic activity by 50% or more at a concentration of 20 M. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20 M, which is physiologically relevant in comparison with the K of dehydroepiandrosterone-sulfate (DHEA-S) oxidation (reported to be between 5 and 20 M). We also discovered that paritaprevir is a time-dependent inhibitor of CYP3A7, which shifts the IC ∼twofold from 11 M to 5 M. Upon further characterization, paritaprevir inactivates DHEA-S metabolism by CYP3A7, with K and K values of 4.66 M and 0.00954 minute, respectively. Depending on treatment plan and off-label drug use, HCV treatment could adversely affect the fetal-maternal communication axis by blocking fetal CYP3A7 metabolism of important endogenous hormones. SIGNIFICANCE STATEMENT: The prevalence of HCV in pregnant people is estimated at between 1% and 8% of the global population, yet little to no information exists about the risk antiviral treatment poses to the developing fetus. There is a potential risk of drugs adversely affecting mother-fetal communication by inhibiting fetal hepatic CYP3A7, an integral enzyme for estriol production. We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development.
丙型肝炎病毒（HCV）对孕妇及其发育中的胎儿构成极大威胁，但尚未制定 HCV 抗病毒治疗指南。虽然 HCV 抗病毒药物的开发取得了实质性进展，但它们对发育中胎儿的影响仍未得到明确界定。这些药物中的许多通过细胞色素 P450 CYP3A 途径代谢，该途径由胎儿和发育中的婴儿中的细胞色素 P450 3A7（CYP3A7）介导。在这项研究中，我们试图研究 HCV 抗病毒药物对 CYP3A7 代谢的影响，因为这种 CYP 酶在胎儿和新生儿的正常发育中起着至关重要的作用。在我们研究的 13 种 HCV 抗病毒药物中，有 8 种（约 62%）在 20μM 浓度下使 CYP3A7 代谢活性抑制 50%或更多。此外，帕立瑞韦、阿舒瑞韦、西美瑞韦、达诺瑞韦和格卡瑞韦的半数最大抑制浓度（IC50）均在 10μM 至 20μM 之间，与脱氢表雄酮硫酸酯（DHEA-S）氧化的 K 值（报告为 5μM 至 20μM）具有生理相关性。我们还发现，帕立瑞韦是 CYP3A7 的时间依赖性抑制剂，将 IC 值从 11μM 左右转变为 5μM。进一步表征后，帕立瑞韦通过 CYP3A7 使 DHEA-S 代谢失活，K 值和 K 值分别为 4.66μM 和 0.00954 分钟。根据治疗方案和非标签药物使用情况，HCV 治疗可能会通过阻断胎儿 CYP3A7 对重要内源性激素的代谢，对胎儿-母体通讯轴产生不利影响。意义声明：在全球人群中，估计有 1%至 8%的孕妇患有 HCV，但有关抗病毒治疗对发育中胎儿的风险几乎没有信息。药物通过抑制胎儿肝 CYP3A7 而对母体-胎儿通讯产生不利影响的潜在风险，CYP3A7 是雌三醇产生的重要酶。我们发现五种 HCV 抗病毒药物抑制了 DHEA-S 通过 CYP3A7 的代谢，而帕立瑞韦使该酶失活。我们的研究表明，这些药物对胎儿正常发育构成潜在威胁。
Zotero 插件
