Can COVID-19 have a clinically significant effect on drug metabolism?

KEYWORDS:

• Bipolar disorder
• cognition
• COVID-19
• CYP450
• cytokines
• depression
• drug metabolism
• inflammation
• liver
• long COVID
• mood disorders
• pharmacokinetics
• pharmacology
• pharmacovigilance
• population health
• post-COVID-19 condition
• prevention
• SARS-CoV-2
• tolerability
• treatment
• vaccination

1. Introduction

Hepatic metabolism is one of three major routes of drug elimination. Drug metabolism generally involves a sequence of two reactions that allow for efficient excretion by the kidneys. Phase I reactions are catabolic and typically involve reduction, oxidation, or hydrolysis to convert lipophilic agents into more polar and reactive products. Phase II reactions are anabolic and consist of conjugation reactions with endogenous hydrophilic substances to further polarize and usually inactivate the parent drug [1]. The Cytochrome P450 (CYP450) enzymes, a set of heme proteins, frequently catalyze reactions involved in phase I metabolism. Although there exist 57 CYP isoforms in humans, not all are involved in drug metabolism, and CYP3A4/5, CYP2D6, CYP2C8/9, and CYP1A2 are responsible for the majority of reactions catalyzed by CYP450 [2]. Herein, we aim to explore the possibility of whether COVID-19 infection and associated inflammation can affect drug metabolism.

2. Inflammation and drug metabolism

The clearance of a given agent varies widely between individuals as pharmacokinetics are affected by age, sex, hereditary and genetic factors, disease states, diet and nutrition, and/or hormonal changes, among many other factors [1]. Parenthetically, it is well established that the activity of hepatic and extrahepatic CYP450s, as well as other enzymes involved in drug metabolism, is affected by infection and/or increased levels of pro-inflammatory cytokines including, but not limited to, interleukin (IL)-6, IL-1β, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α [3,4]. Elevated circulating levels of select pro-inflammatory cytokines correlate with reduced clearance of some medications [4,5], with implications for tolerability and safety [6].

In the majority of cases, CYP450 expression is reduced and enzyme activity is downregulated in the inflammatory state; however, in other circumstances, CYP isoforms may also be induced [3]. Multiple in vitro studies using primary human hepatocytes (PHHs) and the HepaRG cell line have demonstrated downregulation of CYP450 mRNA (inflammation-mediated decreases in CYP450 activity are often preceded by proportionate decreases in mRNA expression) [3], as well as a reduction in metabolite formation of probe substances. As a proof of principle, anti-cytokine monoclonal antibodies have been shown to reverse the effects of pro-inflammatory cytokine-induced depression of CYP450s, and may thus be administered adjunctively in order to bolster the effects of other medications in inflammatory conditions [7]. Certain CYP450 isoforms in the central nervous system (CNS) are reportedly also affected by the inflammatory state, as demonstrated by both in vitro [8] and in vivo studies [9].

Cases of altered drug metabolism in the infectious state have been widely documented in both animals and humans (including pediatric cases) since the mid 1950s. The first known report of CYP modulation during a host defense response was by Samaras and Dietz in 1953, who noted that the actions of pentobarbital were increased when the reticuloendothelial system was stimulated by trypan blue [3]. Other examples of bacterial, viral, and parasitic infections leading to depression of CYP-dependent drug metabolism are summarized in Table 1 of Renton (2001) [3], and additional cases in humans have been systematically reviewed elsewhere [10]. Furthermore, chronic inflammatory diseases, such as cancer [11], nonalcoholic steatohepatitis (NASH) [12], type 2 diabetes [13], and arthritic disease [3] have been linked to decreased drug metabolism and associated relative increases in plasma concentrations of the active pharmaceutical ingredient [14].

Inflammation-mediated inhibition effects may be isoform-specific insofar as CYP3A4 appears to be more susceptible, as demonstrated by in vitro hepatocyte models. Moreover, it is further reported that CYP2D6 may be relatively less likely to be functionally influenced by circulating inflammatory cytokines [4]. Although regulation likely occurs at multiple levels concurrently (i.e. transcriptional and post-transcriptional), mechanisms implicated involve activation of Nuclear factor kappa B (NF-κB), which may regulate the induction of CYP450s, as well as oxidative stress, as administration of antioxidants appears to prevent this downregulation in the LPS model of inflammation [3,4]. Different cytokines regulate specific CYPs [5], and the degree to which a set level of inflammation downregulates CYP450 activities varies between individuals and disease states [4].

3. Pertinence to long covid

COVID-19 is not infrequently associated with acute increases in pro-inflammatory factors as a function of the host response (i.e. ‘cytokine storm’), which often drive lung and/or multiorgan pathology [15]. It is additionally observed that approximately 14–53% of those that recover from SARS-CoV-2 infection (especially hospitalized individuals) exhibit compromised hepatic function [16], suggesting potentially long-term alteration of drug metabolism and excretion. As discussed by El-Ghiaty et al. (2020) [17], the foregoing is not surprising considering multiple systemic viral infections that primarily target the respiratory tract have been shown to cause collateral damage to the liver (e.g. influenza, herpesviruses, SARS, and parvovirus) [18,19].

Indeed, multiple cases of impaired drug metabolism have been reported in individuals with acute COVID-19, both of medications administered for the treatment of COVID-19 (e.g. lopinavir and darunavir), and those indicated for comorbid conditions [17,20,21]. The underlying pathophysiology of impaired drug metabolism in the foregoing cases are thought to include the effects of inflammation on the liver (as discussed previously), and hepatocellular injury occurring due to direct viral invasion of the liver (i.e. hepato-tropism occurring via angiotensin-converting enzyme 2 [ACE2] receptors) and/or medications used in the management of COVID-19 (e.g. hepatotoxic antipyretic agents, antivirals, antibiotics, and/or steroids). Hepatocellular injury secondary to COVID-19 is evidenced by elevated liver enzymes (e.g. alanine transaminase [ALT], aspartate transaminase [AST], and alkaline phosphatase [ALP]).

Emerging evidence indicates that a subset of individuals exhibit prolonged immune dysregulation, including, but not limited to, elevated levels of circulating and CNS proinflammatory factors, autoantibodies, and alterations in T and B cell populations, following resolution of the acute phase of disease [22–24]. The World Health Organization (WHO) defines ‘post-COVID-19 condition’ as persistent symptoms usually occurring 3 months from onset in individuals with past confirmed or probable SARS-CoV-2 infection and persisting for at least 2 months which cannot be explained by an alternative diagnosis [25]. Some researchers have proposed that chronic inflammation is a hallmark of post-COVID-19 condition (long COVID) in a subset of patients, and may subserve or exacerbate certain characteristic symptoms of the condition, including cognitive impairment and fatigue [22,24].

The foregoing immune-inflammatory disturbances raise the question of whether individuals with post-COVID-19 condition may exhibit alterations in drug metabolism, particularly a decreased capacity to metabolize drugs, as a result of direct or indirect effects on CYP450. Depressed CYP450 activity may lead to decreased tolerability and/or altered efficacy (in the cases of medications that are activated by hepatic enzymes) in long COVID patients. Moreover, the extent to which pharmacokinetics are affected may be clinically relevant in subsets of patients due to compromised efficacy or increased risk of tolerability and safety issues.

4. Conclusion and future directions

The consideration of whether individuals with post-COVID-19 condition exhibit a decreased capacity for drug biotransformation is topical given that hundreds of pharmacologic agents are currently being trialed, both formally (i.e. via clinical trials) [26] and informally (i.e. off label use) to treat aspects of the condition and manage associated symptoms. For example, the metabolism of antidepressants such as selective serotonin uptake inhibitors (SSRIs) (e.g. fluvoxamine), and tricyclic antidepressants (TCAs), frequently prescribed for the management of neuropathic pain, cognitive deficits, and mood symptoms, may be particularly affected as many of these agents are substrates of CYP450. Parenthetically, fluvoxamine, which is currently being trialed for the treatment of long COVID [27], is a pan-CYP450 inhibitor in and of itself.

Furthermore, medications metabolized primarily by CYP3A4, as well as those with narrow therapeutic indices and/or safety concerns in situations of decreased functional activity (e.g. Valbenazine), and decreased CYP2D6 activity, may be particularly affected by post-COVID-19 condition. Taking into account that individuals with chronic inflammatory conditions (e.g. diabetes, cardiovascular disease, mood disorders) [28] are at a greater risk of experiencing a severe COVID-19 episode, and may be at an increased risk of developing post-COVID-19 condition, the efficacy and tolerability of medications used to manage the foregoing conditions should be closely monitored post-infection. Taken together, a clarion call is warranted for researchers to characterize the effect of COVID-19-induced inflammation on the pharmacokinetics of medications and its implications for their effectiveness and safety.

Declaration of interests

RS McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. RS McIntyre is a CEO of Braxia Scientific Corp. JD Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund, and Timeposters Fellowship and industry funding for speaker/consultation/research fees from Janssen, Allergan, Lundbeck, Sunovion, and COMPASS. He is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

RS McIntyre and F Ceban conceptualized editorial. F Ceban drafted the manuscript with input from RS McIntyre. All authors provided critical review for important intellectual content and approved the final version of the manuscript.

Additional information

Funding

This paper was not funded.