Remdesivir is an RNA polymerase inhibitor. Clinical trials have shown that the medication has reversible hepatotoxicity and linear pharmacokinetics. Its metabolism has not been fully studied. However, as a substrate of CYP3A4 it is likely that there could be a decrease in remdesivir elimination due to the downregulation of CYP3A4 by inflammatory mediators. With the dosing schedule of remdesivir in COVID-19 patients there is a risk of an unpredictable dose-toxicity relationship and nonlinear pharmacokinetics due to the implementation of a loading dose followed up by infusions. The pharmacokinetics of the drug becomes dose dependent.  Favipiravir is also an RNA polymerase inhibitor but, unlike remdesivir, it is not metabolized by CYP enzymes and no significant effect on the disposition of COVID-19 patients is expected at this time. 


Remdesivir/Favipiravir

Protease inhibitors like lopinavir and ritonavir have been used in COVID-19 patients. They are substrates of CYP3A4 so it is likely they will be present at high plasma concentrations during infection. In addition, these drugs are known to inhibit CYP3A4 and induce other CYPs which can affect the metabolism of other drugs as well. Furthermore, they are known to cause hepatotoxicity regardless which could add to liver injury during COVID-19 infection. 

Lopinavir/Ritonavir

Chloroquine and hydroxychloroquine are antimalarials that have been shown to be effective in targeting the coronavirus by inhibiting viral entry into the cells. However, the efficacy of these drugs was questionable and they are known to be extremely toxic. They are mainly metabolized by CYP3A4 and 2D6 so the suppression of 3A4 would push metabolism to 2D6 which is highly polymorphic. This means there are varying forms of the enzyme with different activities which could cause dangerous drug effects depending on the form the patient has. 


Chloroquine/Hydroxychloroquine 

Rutgers University

Cytokine storm has been common in SARS-CoV-2 virus infection. It involves the overproduction and release of inflammatory cytokines resulting in the recruitment of a large amount of immune cells and causing an immune response so strong it can result in organ damage and failure. In COVID-19 it has been noted that there is potential injury to the liver as a result of this powerful immune response. Since even small changes in liver function affect the clearance and metabolism of substances in the body, it would not be strange to see this effect in COVID-19 patients. In fact, in previous research on viral infection the inflammatory response has caused a suppression of CYP enzymes, enzymes primarily in the liver that are responsible for the metabolism of numbers substances in and that enter the body. It would not completely wrong to assume that this will affect medication taken by those positive for COVID-19 whether that medication is for treating the disease or for other conditions they previously had. This will affect the dosing and whether or not certain drugs should even continue to be used in the patient. Furthermore, those with comorbidities like diabetes and hypertension are much more likely to contract COVID-19 and the medications they are on to treat these conditions could be affected.

Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients

One of the known reactions of COVID-19 is their powerful immune response in defense of the virus. In fact, one of the most common issues in severe patients is organ failure due to the high levels of inflammatory mediators and the virus itself causing damage to the cells. The mediators would cause scarring, ischemic, and necrosis of organ tissues. Commonly the lungs, heart and kidneys fail during severe COVID-19 infections. There have also been significant differences in cytokine levels based on the severity of infection meaning there will be additional differences in drug toxicity between patients based on their disease severity.


Increased Inflammation in COVID-19 patients

The liver is one of the major organs targeted by SARS-CoV-2. The S protein of the virus binds to ACE2 receptors to enter host cells in the body. ACE2 is expressed in the liver so the organ is likely affect by both a direct attack from the virus and damage from an overexpression of proinflammatory mediators. To monitor liver health the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is generally used, both being factors indicative of liver damage when at high levels. This ratio can indicate the liver advancing to cirrhosis or fibrosis.  In studies of COVID-19 patients it was found that levels of markers of liver function were up to five times more than the upper limits of their normal levels and sometimes even higher. In COVID-19 patients that had passed away, about 78% had high levels of markers of abnormal liver function. With the function of the liver in metabolism and protein production, even small changes in the liver that come with the infection may negatively impact the body's response. By altering liver metabolism, there will be consequences seen in the therapeutic and toxic effects of endogenous substances like the medications being taken by COVID-19 patients.

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