Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Mol Pharm. 2023 Sep 4;20(9):4597-4610. doi: 10.1021/acs.molpharmaceut.3c00314. Epub 2023 Aug 1.
The pharmacokinetic alteration of an antimicrobial medication leading to sub-therapeutic plasma level can aid in the emergence of resistance, a global threat nowadays. In this context, molnupiravir (prodrug of EIDD-1931) is the most efficacious orally against corona virus disease (COVID-19). In addition to drug-drug interaction, the pharmacokinetics of a drug can significantly vary during any disease state, leading to disease-drug interaction. However, no information is available for such a recently approved drug. Therefore, we aimed to explore the oral pharmacokinetics of EIDD-1931 in seven chemically induced disease states individually compared to the normal state using various rat models. Induction of any disease situation was confirmed by the disease specific study(s) prior to pharmacokinetic investigations. Compared to the normal state, substantially lowered plasma exposure (0.47- and 0.63-fold) with notably enhanced clearance (2.00- and 1.56-fold) of EIDD-1931 was observed in rats of ethanol-induced gastric injury and carbon tetrachloride-induced liver injury states. Conversely, paclitaxel-induced neuropathic pain and cisplatin-induced kidney injury states exhibited opposite outcomes on oral exposure (1.43- and 1.50-fold) and clearance (0.69- and 0.65-fold) of EIDD-1931. Although the highest plasma concentration (2.26-fold) markedly augmented in the doxorubicin-induced cardiac injury state, streptozocin-induced diabetes and lipopolysaccharide-induced lung injury state did not substantially influence the pharmacokinetics of EIDD-1931. Exploring the possible phenomenon behind the reduced or boosted plasma exposure of EIDD-1931, results suggest the need for dose adjustment in respective diseased conditions in order to achieve desired efficacy during oral therapy of EIDD-1931.
抗菌药物药代动力学的改变导致治疗浓度的血浆水平降低，可能会助长耐药性的产生，这是当今全球面临的威胁。在这种情况下，莫努匹韦（EIDD-1931 的前药）是目前最有效的口服抗冠状病毒病（COVID-19）药物。除了药物相互作用外，在任何疾病状态下，药物的药代动力学都会发生显著变化，从而导致疾病-药物相互作用。然而，对于这种最近批准的药物，尚无相关信息。因此，我们旨在使用各种大鼠模型单独研究七种化学诱导的疾病状态下 EIDD-1931 的口服药代动力学，与正常状态进行比较。在进行药代动力学研究之前，通过特定的疾病研究来确认任何疾病情况的诱导。与正常状态相比，在乙醇诱导的胃损伤和四氯化碳诱导的肝损伤大鼠中，EIDD-1931 的血浆暴露显著降低（0.47-和 0.63 倍），清除率显著增加（2.00-和 1.56 倍）。相反，紫杉醇诱导的神经病理性疼痛和顺铂诱导的肾损伤大鼠的 EIDD-1931 口服暴露（1.43-和 1.50 倍）和清除率（0.69-和 0.65 倍）则呈现相反的结果。虽然在多柔比星诱导的心脏损伤大鼠中，EIDD-1931 的最高血浆浓度（2.26 倍）显著增加，但链脲佐菌素诱导的糖尿病和脂多糖诱导的肺损伤大鼠并没有显著影响 EIDD-1931 的药代动力学。探索 EIDD-1931 血浆暴露降低或增加的可能现象表明，在口服 EIDD-1931 治疗时，需要根据不同的疾病情况调整剂量，以达到所需的疗效。
