Department of Pharmacotherapy and Translational Research, Gainesville, FL, USA.
Department of Pharmacotherapy and Translational Research, Gainesville, FL, USA; Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL, USA.
Chem Biol Interact. 2022 Sep 25;365:110097. doi: 10.1016/j.cbi.2022.110097. Epub 2022 Aug 11.
Remdesivir (RDV, Veklury®) is an FDA-approved prodrug for the treatment of hospitalized patients with COVID-19. Recent in vitro studies have indicated that human carboxylesterase 1 (CES1) is the major metabolic enzyme catalyzing RDV activation. COVID-19 treatment for hospitalized patients typically also involves a number of antibiotics and anti-inflammatory drugs. Further, individuals who are carriers of a CES1 variant (polymorphism in exon 4 codon 143 [G143E]) may experience impairment in their ability to metabolize therapeutic agents which are CES1 substrates. The present study assessed the potential influence of nine therapeutic agents (hydroxychloroquine, ivermectin, erythromycin, clarithromycin, roxithromycin, trimethoprim, ciprofloxacin, vancomycin, and dexamethasone) commonly used in treating COVID-19 and 5 known CES1 inhibitors on the metabolism of RDV. Additionally, we further analyzed the mechanism of inhibition of cannabidiol (CBD), as well as the impact of the G143E polymorphism on RDV metabolism. An in vitro S9 fraction incubation method and in vitro to in vivo pharmacokinetic scaling were utilized. None of the nine therapeutic agents evaluated produced significant inhibition of RDV hydrolysis; CBD was found to inhibit RDV hydrolysis by a mixed type of competitive and noncompetitive partial inhibition mechanism. In vitro to in vivo modeling suggested a possible reduction of RDV clearance and increase of AUC when coadministration with CBD. The same scaling method also suggested a potentially lower clearance and higher AUC in the presence of the G143E variant. In conclusion, a potential CES1-mediated DDI between RDV and the nine assessed medications appears unlikely. However, a potential CES1-mediated DDI between RDV and CBD may be possible with sufficient exposure to the cannabinoid. Patients carrying the CES1 G143E variant may exhibit a slower biotransformation and clearance of RDV. Further clinical studies would be required to evaluate and characterize the clinical significance of a CBD-RDV interaction.
瑞德西韦（RDV，Veklury®）是一种经美国食品药品监督管理局批准的前药，用于治疗住院的 COVID-19 患者。最近的体外研究表明，人类羧酸酯酶 1（CES1）是催化 RDV 激活的主要代谢酶。COVID-19 住院患者的治疗通常还涉及多种抗生素和抗炎药物。此外，携带 CES1 变体（外显子 4 密码子 143 [G143E] 中的多态性）的个体可能会在代谢 CES1 底物的治疗剂的能力方面受损。本研究评估了九种常用于治疗 COVID-19 的治疗药物（羟氯喹、伊维菌素、红霉素、克拉霉素、罗红霉素、甲氧苄啶、环丙沙星、万古霉素和地塞米松）和五种已知的 CES1 抑制剂对 RDV 代谢的潜在影响。此外，我们进一步分析了大麻二酚（CBD）的抑制机制，以及 G143E 多态性对 RDV 代谢的影响。利用体外 S9 级分孵育方法和体外至体内药代动力学缩放方法进行研究。评估的九种治疗药物中没有一种对 RDV 水解产生显著抑制作用；CBD 被发现通过混合竞争性和非竞争性部分抑制机制抑制 RDV 水解。体外至体内建模表明，与 CBD 联合给药时，可能会降低 RDV 清除率并增加 AUC。相同的缩放方法还表明，在存在 G143E 变体的情况下，清除率可能会降低，AUC 会升高。总之，RDV 与评估的九种药物之间可能不存在 CES1 介导的药物相互作用。然而，RDV 与 CBD 之间可能存在 CES1 介导的药物相互作用，并且存在足够的大麻素暴露。携带 CES1 G143E 变体的患者可能表现出较慢的生物转化和 RDV 清除率。需要进一步的临床研究来评估和表征 CBD-RDV 相互作用的临床意义。
