Inflammation-mediated Phenoconversion: A Potential Threat to COVID-19 Pharmacotherapy

Abstract

One of the important hallmarks of coronavirus disease 2019 (COVID-19) is the existence of severe inflammatory responses. Many reports indicated that inflammatory mediators might suppress the biological functions of some drug metabolizing enzymes and transporters, and therefore result in a transient mismatch between their genotype and phenotype expressions, a phenomenon which is called phenoconversion. The incidence might be clinically relevant to the COVID-19 patients with comorbidities. The patients are treated with multiple drugs that are prone to be altered pharmacokinetically by inflammation-mediated phenoconversion, leading to the modification of their effectiveness and safety. In this review, we discuss the regulation of inflammatory responses during COVID-19 infection and the evidence as well as potential mechanisms of inflammation-mediated phenoconversion. We also provide possible clinical implications of such phenoconversion events as a potential threat in the management of COVID-19 patients.

The Impact of Inflammation and Drug Interactions on Covid-19 Pharmacotherapy. A Mini-Review

“…An important aspect of inflammatory responses in patients with COVID-19 is the suppression of the biological activities of drug metabolising enzymes and transporters [3]. This phenomenon could generate a transient mismatch between their expressions and genotypephenotype, a phenomenon named phenoconversion.…”

“…Therefore, it is important to identify patients who are prone to be affected by inflammation-mediated phenoconversion, as well as potentially affected drugs in this situation. They also need to be aware of the potential impact of inflammation-mediated phenoconversion and therefore to monitor more closely the potential side effects of certain medicines and, if necessary, to adjust the dose of the drugs [3].…”

“…Coronavirus replication probably activates the defence system of host cells, which increases the production of antiviral proteins (interferon) and the subsequent release of various types of proinflammatory cytokines [24]. It has been observed that in patients with severe COVID-19, levels of proinflammatory cytokines, such as interleukins (IL-2, IL-6, IL-7, IL-8, IL-10), tumour necrosis factor (TNF)-α, granulocyte colonystimulating factor (GCSF), interferon gammainduced protein (IP)-10, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α, have levels increased, suggesting a possible correlation between elevated levels of proinflammatory cytokines and the severity of this condition [3]. In coronavirus infection, these locally synthesized cytokines can circulate through the bloodstream and lead to a systemic effect due to the interaction with cell membrane receptors, vascular endothelial transporters and parenchymal cells in many organs.…”