Bhardwaj Mahir, Kour Dilpreet, Rai Garima, Bhattacharya Srija, Manhas Diksha, Vij Bhavna, Kumar Ajay, Mukherjee Debaraj, Ahmed Zabeer, Gandhi Sumit G, Nandi Utpal
Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
ACS Omega. 2024 Mar 15;9(12):13982-13993. doi: 10.1021/acsomega.3c09287. eCollection 2024 Mar 26.
EIDD-1931 is the active form of molnupiravir, an orally effective drug approved by the United States Food and Drug Administration (USFDA) against COVID-19. Pharmacokinetic alteration can cause untoward drug interaction (drug-drug/disease-drug), but hardly any information is known about this recently approved drug. Therefore, we first investigated the impact of the arthritis state on the oral pharmacokinetics of EIDD-1931 using a widely accepted complete Freund's adjuvant (CFA)-induced rat model of rheumatoid arthritis (RA) after ascertaining the disease occurrence by paw swelling measurement and X-ray examination. Comparative oral pharmacokinetic assessment of EIDD-1931 (normal state vs arthritis state) showed that overall plasma exposure was augmented (1.7-fold) with reduced clearance (0.54-fold), suggesting its likelihood of dose adjustment in arthritis conditions. In order to elucidate the effect of EIDD-1931 treatment at a therapeutic regime (normal state vs arthritis state) on USFDA-recommended panel of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) for drug interaction using the same disease model, we monitored protein and mRNA expressions (rat homologs) in liver tissue by western blotting (WB) and real time-polymerase chain reaction (RT-PCR), respectively. Results reveal that EIDD-1931 treatment could strongly influence CYP3A4 and CYP2C8 among experimental proteins/mRNAs. Although CYP2C8 regulation upon EIDD-1931 treatment resembles similar behavior under the arthritis state, results dictate a potentially reverse phenomenon for CYP3A4. Moreover, the lack of any CYP inhibitory effect by EIDD-1931 in human/rat liver microsomes (HLM/RLM) helps to ascertain EIDD-1931 treatment-mediated disease-drug interaction and the possibility of drug-drug interaction with disease-modifying antirheumatic drugs (DMARDs) upon coadministration. As elevated proinflammatory cytokine levels are prevalent in RA and nuclear factor-kappa B (NF-kB) and nuclear receptors control CYP expressions, further studies should focus on understanding the regulation of affected CYPs to subside unexpected drug interaction.
EIDD-1931是莫努匹拉韦的活性形式，莫努匹拉韦是一种经美国食品药品监督管理局（USFDA）批准用于治疗新冠病毒肺炎的口服有效药物。药代动力学改变可能导致不良药物相互作用（药物-药物/疾病-药物），但对于这种最近获批的药物，人们几乎一无所知。因此，我们首先通过爪肿胀测量和X线检查确定疾病发生后，使用广泛认可的完全弗氏佐剂（CFA）诱导的类风湿性关节炎（RA）大鼠模型，研究关节炎状态对EIDD-1931口服药代动力学的影响。EIDD-1931（正常状态与关节炎状态）的比较口服药代动力学评估表明，总体血浆暴露增加（1.7倍），清除率降低（0.54倍），这表明在关节炎情况下可能需要调整剂量。为了使用相同的疾病模型阐明治疗剂量的EIDD-1931（正常状态与关节炎状态）对USFDA推荐的细胞色素P450（CYP）酶组（CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4）药物相互作用的影响，我们分别通过蛋白质印迹法（WB）和实时聚合酶链反应（RT-PCR）监测肝组织中的蛋白质和mRNA表达（大鼠同源物）。结果显示，在实验性蛋白质/mRNA中，EIDD-1931治疗可强烈影响CYP3A4和CYP2C8。虽然EIDD-1931治疗对CYP2C8的调节在关节炎状态下表现出类似行为，但结果表明CYP3A4可能出现相反现象。此外，EIDD-1931在人/大鼠肝微粒体（HLM/RLM）中缺乏任何CYP抑制作用，这有助于确定EIDD-1931治疗介导的疾病-药物相互作用以及与改善病情抗风湿药（DMARDs）联合给药时药物-药物相互作用的可能性。由于RA中促炎细胞因子水平升高，且核因子-κB（NF-κB）和核受体控制CYP表达，进一步的研究应集中于了解受影响的CYPs的调节，以减少意外的药物相互作用。
