BREAKING! COVID-19 Drug Strategies Have Been Wrong! SARS-CoV-2 Infections Affects Drug Metabolizing Enzymes And Membrane Transporters In Tissues!

COVID-19 Drugs: It is coming to light that all strategies with regards to treating COVID-19 has been wrong as many missed out certain critical data that affects the pharmacokinetics and pharmacodynamics of these drugs that have been approved so far by various clueless regulatory agencies across the world.


 
A new breakthrough study by researchers from University of Toronto-Canada, OneDrug-Canada, Sunnybrook Research Institute-Canada and Ontario Forensic Pathology Service-Canada has found that SARS-CoV-2 infections affect various drug metabolizing enzymes and membrane transporters (DMETS) including many found in lung tissues and elsewhere in the body of the human host!
 
The study findings have phenomenal implications not only in terms of the drugs that were approved to treat COVID-19 and their usage but also other drugs and medications being used to treat other diseases or conditions in people who have been exposed to SARS-CoV-2!
 
COVID-19 has caused millions of deaths and affected hundreds of millions of people around the world, making it one of the deadliest pandemics in the 21st century. With vaccines not guaranteeing full protection, there is an urgent need for effective antiviral drugs to complement existing vaccines. However, several factors can affect the clinical efficacy and safety of promising COVID-19 drugs, including how the drugs interact with drug metabolizing enzymes and membrane transporters (DMETs) in the lung, the main organ affected by SARS-CoV-2 infection.
 
In this study, the COVID-19 Drugs research team investigated how SARS-CoV-2 infection could dysregulate the expression of clinically relevant DMETs in Vero E6 cells and human lung tissues.
 
The Role of DMETs in Drug Efficacy and Safety
The lung is a complex organ consisting of around 40 different cell types. These cells have varying levels of DMETs expression and activity, which can alter drug concentrations, distribution, and retention in the lungs. Inflammation caused by SARS-CoV-2 infection can also lead to the dysregulation of DMETs.
 
Proinflammatory cytokines such as IL-6 and IL-1β have been implicated in this dysregulation, potentially affecting the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of drugs in COVID-19 patients.
 
Study Objectives and Methodology
The study aimed to investigate whether SARS-CoV-2 infection dysregulates the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Additionally, the researchers assessed the role of inflammatory and regulatory proteins in modulating the dysregulation of DMETs in human lung tissues.
 
Results and Findings
Alarmingly, the study found that SARS-CoV-2 infection dysregulated the expression of CYP3A4 and UGT1A1 at the mRNA level in Vero E6 cells and P-gp and MRP1 at the protein level in postmortem human lung tissues.
 
The study team also found that DMETs could potentially be dysregulated by SARS-CoV-2-associated inflammatory responses and lung injuries at the cellular level.
 
The study also uncovered the pulmonary cellular localization of certain DMETs in human lung tissues and found that the presence of inflammatory cells was the major driving force for differences in DMETs localization between COVID-19 and control human lung tissues.
 
This suggests that SARS-CoV-2 infection could lead to inflammatory responses that activate regulatory proteins, which could then dysregulate the expression of DMETs in lymphocytes. Furthermore, the researchers observed that the presence of inflammatory cells in COVID-19 lung tissues could increase the expression of DMETs, potentially affecting drug PK/PD profiles.
 
SARS-CoV-2-infected Vero E6 cells demonstrated dysregulation of the metabolic enzyme involved in the disposition of commonly prescribed COVID-19 drugs
SARS-CoV-2 infection in Vero E6 cells leads to changes in the regulation of metabolic enzymes involved in the breakdown of common COVID-19 drugs. CYP3A4, an enzyme that processes dexamethasone and nirmatrelvir, is upregulated, while UGT1A1 is downregulated. These changes could impact the effectiveness of these medications in treating COVID-19. Inflammatory responses might also alter the pharmacokinetic profiles of drugs like remdesivir, potentially explaining varying clinical outcomes. Proper dosing and treatment plans for remdesivir are still under investigation.
 
Caution should be exercised when prescribing medications to COVID-19 patients, particularly those with comorbidities, to avoid harmful interactions. For instance, UGT1A1, which is important for processing irinotecan, a chemotherapy drug, could be affected in patients with both COVID-19 and lung cancer.
 
Altered mRNA expression of DMETs, which help metabolize medications, has been observed in primary cultures of human hepatocytes under the influence of proinflammatory cytokines. The lack of dysregulation of these DMETs in SARS-CoV-2-infected Vero E6 cells may be due to differences in species and organ expression. Further investigation is needed to better understand these interactions and their impact on COVID-19 treatment.
 
DMETs are expressed in several human pulmonary cells affected by SARS-CoV-2 infection
The study was also the first to localize the cellular expression of uptake transporters ENT1 and ENT2, as well as CYP1A2, CYP2C8, CYP2C9, and CYP2D6 in human lung tissues through immunohistochemistry (IHC). The researchers found that ENT1 and ENT2 were primarily present in inflammatory cells of lung tissues in COVID-19 patients, making them potentially vulnerable to SARS-CoV-2-mediated increases in expression. ENT1 and ENT2 are involved in the uptake of COVID-19 drugs like remdesivir and molnupiravir, and their dysregulation may partly explain the limited and variable clinical efficacy observed for remdesivir.
 
The study also reported the pulmonary cellular localization of CYP2B6, CYP2C8, CYP2C19, and CYP3A4. Contrary to earlier findings, the researchers observed BCRP localization in the cytoplasm of endothelial cells and P-gp localization in alveolar epithelial cells. Additionally, they found MRP1 expression in the cytoplasm and nucleus of alveolar epithelial cells, while MRP2 was predominantly localized in the circumferential membrane compartment.
The study revealed that some drug-metabolizing enzymes and transporters (DMETs) were localized in atypical cellular compartments, indicating that further research is needed to understand how this might affect their structure and function.
 
Conclusions and Recommendations
This study is the first to show that SARS-CoV-2 infection dysregulates clinically relevant drug metabolizing enzymes and membrane transporters in Vero E6 cells and human lung tissues.
 
The study findings suggest that the dysregulation of DMETs could potentially affect the safety and efficacy of promising COVID-19 drugs and lead to unexpected adverse drug reactions in COVID-19 patients with multiple medications.
 
The researchers recommend further investigation into SARS-CoV-2-mediated dysregulation of human pulmonary DMETs and its potential implications on controlling the safety and efficacy of promising COVID-19 drugs. They also call for more research on the spatial distribution and disposition of COVID-19 drugs at the cellular level in human lung tissues.
 
The study also highlighted the importance of the alveolar epithelial cells and lymphocytes, which are both sites of SARS-CoV-2 infection and localization of DMETs. Understanding the interplay between the virus, inflammatory response, and DMETs in these cells is crucial for optimizing COVID-19 drug dosing regimens and improving clinical outcomes. This is particularly relevant for patients with multiple medications, as SARS-CoV-2-associated changes in DMETs expression may lead to unforeseen drug-drug interactions or altered drug responses, potentially worsening the patient's condition.
 
The study provides valuable insights into the potential impact of SARS-CoV-2 infection on the expression and localization of DMETs in lung tissues. These findings may have important implications for the development and optimization of COVID-19 drug therapies.
 
The study findings were published in the peer reviewed journal: Frontiers in Pharmacology. https://www.frontiersin.org/articles/10.3389/fphar.2023.1124693/full
 
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