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

Abstract

Coronavirus Disease 2019 (COVID-19) has been a global health crisis since it was first identified in December 2019. In addition to fever, cough, headache, and shortness of breath, an intense increase in immune response-based inflammation has been the hallmark of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) virus infection. This narrative review summarizes and critiques pathophysiology of COVID-19 and its plausible effects on drug metabolism and disposition. The release of inflammatory cytokines (e.g., interleukins, tumor necrosis factor α), also known as ‘cytokine storm’, leads to altered molecular pathophysiology and eventually organ damage in the lung, heart, and liver. The laboratory values for various liver function tests (e.g., alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin) have indicated potential hepatocellular injury in COVID-19 patients. Since the liver is the powerhouse of protein synthesis and the primary site of cytochrome P450 (CYP)-mediated drug metabolism, even a minor change in the liver function status has the potential to affect the hepatic clearance of xenobiotics. It has now been well established that extreme increases in cytokine levels are common in COVID-19 patients, and previous studies with patients infected with non-SARS-CoV-2 virus have shown that CYP enzymes can be suppressed by an infection-related cytokine increase and inflammation. Alongside the investigational COVID-19 drugs, the patients may also be on therapeutics for comorbidities; especially epidemiological studies have indicated that individuals with hypertension, hyperglycemia, and obesity are more vulnerable to COVID-19 than the average population. This complicates the drug-disease interaction profile of the patients as both the investigational drugs (e.g., remdesivir, dexamethasone) and the agents for comorbidities can be affected by compromised CYP-mediated hepatic metabolism. Overall, it is imperative that healthcare professionals pay attention to the COVID-19 and CYP-driven drug metabolism interactions with the goal to adjust the dose or discontinue the affected drugs as appropriate.

Risks of potential drug–drug interactions in COVID-19 patients treated with corticosteroids: a single-center experience

“…Accordingly, it cannot be excluded that DDIs predicted to be moderate in SARS-CoV-2-uninfected patients might eventually become clinically relevant in some phases of the COVID-19 disease. Indeed, during the active phase of SARS-CoV-2 infection, pro-inflammatory cytokines are likely to downregulate the activity of liver enzymes, eventually counterbalancing the well-known inductive effect of corticosteroids on drug metabolism [ 9 ]. However, when the inflammatory phase ends, corticosteroid-related DDIs may be revealed, raising potential clinical challenges.…”

ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential

“…As such, there are 57 isoforms of human CYP enzymes that are responsible for the biotransformation of endobiotic and xenobiotic substances including COVID-19 medications [ 36 ]. CYP3A4 is a critical enzyme that is responsible for about 70% of the drugs available in the clinic [ 37 ]. However, there are additional major CYP enzymes including CYP2C9, CYPC19, CYP2C8, CYP2D6, and CYP1A2 [ 35 ].…”

“…In terms of CYP-related interactions with remdesivir, there are ample opportunities of modulating remdesivir metabolism due to the CYP inducers and inhibitors administered in COVID-19 patients [ 37 ]. Though CYP3A4 is reported to have about 10% contribution in the metabolism of remdesivir [ 65 ], depending on the relative status of non-CYP metabolizing enzyme activities, CYP3A4 may contribute to a higher extent.…”

Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions

“…This indicated that remdesivir PK profile could be variable depending on the status of the COVID-19 patients. Several clinical studies have suggested that liver and renal functions are potential compromised during the severe COVID-19 which can alter remdesivir PK (1,40,42).…”

“…Due to its emergent nature, there are limited treatment options available against the coronavirus disease of 2019 . Treatment regimens against COVID-19 focus on preventing replication of the virus as well as managing inflammation and other symptoms (1). Chloroquine, hydroxychloroquine, azithromycin, ivermectin, and lopinavir/ritonavir have been used as treatment options against COVID-19 (2).…”