The influence of <scp>SARS‐CoV</scp>‐2 infection on expression of drug‐metabolizing enzymes and transporters in a <scp>hACE2</scp> murine model

Deshpande, Kiran B.; Lange, Keith R.; Stone, William B.; Yohn, Christine N.; Schlesinger, Naomi; Kagan, Leonid; Auguste, Albert J.; Firestein, Bonnie L.; Brunetti, Luigi

doi:10.1002/prp2.1071

Cited by 4 publications

(1 citation statement)

References 58 publications

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“…In this context, it has been documented that the increased proinflammatory cytokines induced by COVID-19 impact drug metabolism as they interfere with the regulation of CYP enzymes and drug transporter expression [68,71,72]. In humans, it has been observed that inflammation caused by COVID-19 reduces CYP3A activity, which, in turn, affects the metabolism of midazolam.…”

Section: Inflammation As a Results Of Infection Modifies Drug Responsementioning

confidence: 99%

Pharmacomicrobiomics and Drug–Infection Interactions: The Impact of Commensal, Symbiotic and Pathogenic Microorganisms on a Host Response to Drug Therapy

Torres-Carrillo,

Martínez-López,

Torres-Carrillo

et al. 2023

IJMS

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Microorganisms have a close relationship with humans, whether it is commensal, symbiotic, or pathogenic. Recently, it has been documented that microorganisms may influence the response to drug therapy. Pharmacomicrobiomics is an emerging field that focuses on the study of how variations in the microbiome affect the disposition, action, and toxicity of drugs. Two additional sciences have been added to complement pharmacomicrobiomics, namely toxicomicrobiomics, which explores how the microbiome influences drug metabolism and toxicity, and pharmacoecology, which refers to modifications in the microbiome as a result of drug administration. In this context, we introduce the concept of “drug-infection interaction” to describe the influence of pathogenic microorganisms on drug response. This review analyzes the current state of knowledge regarding the relevance of microorganisms in the host’s response to drugs. It also highlights promising areas for future research and proposes the term “drug-infection interaction” as an extension of pharmacomicrobiomics.

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Section: Inflammation As a Results Of Infection Modifies Drug Responsementioning

confidence: 99%

Pharmacomicrobiomics and Drug–Infection Interactions: The Impact of Commensal, Symbiotic and Pathogenic Microorganisms on a Host Response to Drug Therapy

Torres-Carrillo,

Martínez-López,

Torres-Carrillo

et al. 2023

IJMS

View full text Add to dashboard Cite

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The influence of SARS‐CoV‐2 infection on expression of drug‐metabolizing enzymes and transporters in a hACE2 murine model

Deshpande

Lange

Stone

et al. 2023

Pharmacology Res & Perspec

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and the resulting Coronavirus disease 2019 emerged in late 2019 and is responsible for significant morbidity and mortality worldwide. A hallmark of severe COVID‐19 is exaggerated systemic inflammation, regarded as a “cytokine storm,” which contributes to the damage of various organs, primarily the lungs. The inflammation associated with some viral illnesses is known to alter the expression of drug‐metabolizing enzymes and transporters. These alterations can lead to modifications in drug exposure and the processing of various endogenous compounds. Here, we provide evidence to support changes in the mitochondrial ribonucleic acid expression of a subset of drug transporters (84 transporters) in the liver, kidneys, and lungs and metabolizing enzymes (84 enzymes) in the liver in a humanized angiotensin‐converting enzyme 2 receptor mouse model. Specifically, three drug transporters (Abca3, Slc7a8, Tap1) and the pro‐inflammatory cytokine IL‐6 were upregulated in the lungs of SARS‐CoV‐2 infected mice. We also found significant downregulation of drug transporters responsible for the movement of xenobiotics in the liver and kidney. Additionally, expression of cytochrome P‐450 2f2 which is known to metabolize some pulmonary toxicants, was significantly decreased in the liver of infected mice. The significance of these findings requires further exploration. Our results suggest that further research should emphasize altered drug disposition when investigating therapeutic compounds, whether re‐purposed or new chemical entities, in other animal models and ultimately in individuals infected with SARS‐CoV‐2. Moreover, the influence and impact of these changes on the processing of endogenous compounds also require further investigation.

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COVID‐19 severity gradient differentially dysregulates clinically relevant drug processing genes in nasopharyngeal swab samples

Nwabufo,

Luc,

McGeer

et al. 2024

Brit J Clinical Pharma

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AimUnderstanding how COVID‐19 impacts the expression of clinically relevant drug metabolizing enzymes and membrane transporters (DMETs) is vital for addressing potential safety and efficacy concerns related to systemic and peripheral drug concentrations. This study investigates the impact of COVID‐19 severity on DMETs expression and the underlying mechanisms to inform the design of precise clinical dosing regimens for affected patients.Methods: Transcriptomics analysis of 102 DMETs, 10 inflammatory markers, and 12 xenosensing regulatory genes was conducted on nasopharyngeal swabs from 50 SARS‐CoV‐2 positive (17 outpatients, 16 non‐ICU, and 17 ICU) and 13 SARS‐CoV‐2 negative individuals, clinically tested through qPCR, in the Greater Toronto area from October 2020 to October 2021.Results: We observed a significant differential gene expression for 42 DMETs, 6 inflammatory markers, and 9 xenosensing regulatory genes. COVID‐19 severity was associated with the upregulation of AKR1C1, MGST1, and SULT1E1, and downregulation of ABCC10, CYP3A43, and SLC29A4 expressions. Altogether, SARS‐CoV‐2‐positive patients showed an upregulation in CYP2C9, CYP2C19, AKR1C1, SULT1B1, SULT2B1, and SLCO4A1 and downregulation in FMO5, MGST3, ABCC5, and SLCO4C1 compared with SARS‐CoV‐2 negative individuals. These dysregulations were associated with significant changes in the expression of inflammatory and xenosensing regulatory genes driven by the disease. GSTM3, PPARA, and AKR1C1 are potential biomarkers of the observed DMETs dysregulation pattern in nasopharyngeal swabs of outpatients, non‐ICU, and ICU patients, respectively.Conclusion: The severity of COVID‐19 is associated with the dysregulation of DMETs involved in processing commonly prescribed drugs, suggesting potential disease–drug interactions, especially for narrow therapeutic index drugs.

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The influence of SARS‐CoV‐2 infection on expression of drug‐metabolizing enzymes and transporters in a hACE2 murine model

Cited by 4 publications

References 58 publications

Pharmacomicrobiomics and Drug–Infection Interactions: The Impact of Commensal, Symbiotic and Pathogenic Microorganisms on a Host Response to Drug Therapy

Pharmacomicrobiomics and Drug–Infection Interactions: The Impact of Commensal, Symbiotic and Pathogenic Microorganisms on a Host Response to Drug Therapy

The influence of SARS‐CoV‐2 infection on expression of drug‐metabolizing enzymes and transporters in a hACE2 murine model

COVID‐19 severity gradient differentially dysregulates clinically relevant drug processing genes in nasopharyngeal swab samples

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