Molecular mechanism for the involvement of CYP2E1/NF-κB axis in bedaquiline-induced hepatotoxicity

Kotwal, Pankul; Khajuria, Parul; Dhiman, Sumit; Kour, Dilpreet; Dhiman, Shakti Kumar; Kumar, Ajay; Nandi, Utpal

doi:10.1016/j.lfs.2023.121375

Cited by 7 publications

(4 citation statements)

References 60 publications

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“…Myocardial necrosis and fibrosis are the pathophysiological hallmarks of cardiac injury. 28,31 Our histopathological examination data demonstrate the occurrence of cardiac damage (Figure 3C,D). Upon oral administration of EIDD-1931 in animals with cardiac injury, we observed a significant enhancement in the C max of EIDD-1931 by 2.3-fold compared to the normal state (Figure 3E and Table 1).…”

Section: Pharmacokinetics Of Eidd-1931 In the Cardiac Injury Statementioning

confidence: 67%

“…Then, experimental tissues were processed by a standard protocol to prepare slides using hematoxylin and eosin (H&E) staining. Slides were monitored for tissue-specific parameters under a light microscope (make: Magnus; model: INVI). , To check protein expression in the brain, the lysate was prepared in radioimmunoprecipitation assay (RIPA) buffer using an equal amount of brain tissue from each animal of the particular study group and the protein expression was studied using the earlier reported protocol for western blotting. , …”

Section: Methodsmentioning

confidence: 99%

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Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Bhardwaj,

Gour,

Ahmed

et al. 2023

Mol. Pharmaceutics

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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.

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Section: Pharmacokinetics Of Eidd-1931 In the Cardiac Injury Statementioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Bhardwaj,

Gour,

Ahmed

et al. 2023

Mol. Pharmaceutics

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“…WB was performed to check the protein expression of CYP1A2, CYP2B6, CYP2C8, CYP2C11, CYP2C19, CYP2D6, and CYP3A4 in the experimental liver tissues (equal proportion from each animal) of various study groups using the standard immunoblotting protocol. , The present study was carried out using β-actin as a loading control, which is widely used by several researchers for WB analysis. − The tissue homogenate was prepared using radioimmunoprecipitation assay (RIPA) buffer and protein content was determined using the Bradford method. The protein was separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), transferred onto polyvinylidene fluoride (PVDF) membranes, blocked with skimmed milk (5% w/v), and probed with specific primary antibody (∼14 h at 4 °C).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

EIDD-1931 Treatment Tweaks CYP3A4 and CYP2C8 in Arthritic Rats to Expedite Drug Interaction: Implication in Oral Therapy of Molnupiravir

Bhardwaj,

Kour,

Rai

et al. 2024

ACS Omega

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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.

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Unveiling the Hub Genes Involved in Cadmium-Induced Hepatotoxicity

Yang,

Wang,

Wang

et al. 2024

Biol Trace Elem Res

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Molecular mechanism for the involvement of CYP2E1/NF-κB axis in bedaquiline-induced hepatotoxicity

Cited by 7 publications

References 60 publications

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

EIDD-1931 Treatment Tweaks CYP3A4 and CYP2C8 in Arthritic Rats to Expedite Drug Interaction: Implication in Oral Therapy of Molnupiravir

Unveiling the Hub Genes Involved in Cadmium-Induced Hepatotoxicity

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