The impact of COVID-19 infection on cytochrome P450 3A4-mediated drug metabolism and drug interactions

Figures & data

Figure 1. Simplified overview of hepatic CYP3A4 regulation by SARs-CoV-2 infection. This figure was adapted with permission from figure 1 in McColl et al [5]. Virulence factors from the SAR-CoV-2 virus interact with the host tissue epithelium and tissue resident macrophages to stimulate cytokine (e.g. interleukin (IL) −1b and IL-6 and tumor necrosis factor (TNF) release as part of the innate immune response. In turn, the cytokines, bind to their respective receptors on hepatocytes to activate intracellular signaling pathways that inhibit (-) the transcription of the CYP3A4 gene. This results in a reduction of CYP3A4 mRNA and ultimately lower amounts of the CYP3A4 enzyme. The consequence is reduced hepatic CYP3A4 metabolism leading to increased plasma concentrations of substrate drugs. Simultaneous administration of potent CYP3A4 inhibitors, is predicted to lead to further reductions in CYP3A4-mediated drug metabolism. Additional mechanisms of CYP3A4 regulation are not shown and include epigenetic regulation and post-transcriptional regulation. For further details the reader is referred to the article by McColl et al [5].

Table 1. Summary of main findings from studies evaluating the effects of COVID-19 on CYP3A4 expression and function.

Authors/year	Study design and main findings	Ref
Rasool et al., 2021	Meta-analysis of Gene Expression Omnibus (GEO) data on the livers of deceased COVID-19 patients (n = 4) versus livers (n = 6) from patients with nonalcoholic fatty liver disease (controls). Hepatic CYP3A4 expression was reduced by −13.89 log2 units (>99.99%) in COVID-19 patients compared to controls.	[11]
Lenoir et al., 2021	Prospective analysis of hepatic CYP 1A2, 2B6, 2C9, 2C19, 2D6 and 3A4 activity using a phenotyping cocktail in 27 hospitalized adults with moderate to severe COVID-19 during infection and 3 months after. Mean CRP, IL6 and TNF were significantly increased 38, 8.5 and 1.7-fold, respectively, during infection compared to 3 months after. Mean OH-midazolam/midazolam ratio (CYP3A4 activity measure) was 0.43 (22% lower) during infection compared to 0.55 three months after, p < 0.05.	[4]
Smeets et al., 2022	Prospective steady-state population PK analysis of midazolam in 31 mechanically ventilated adult COVID-19 patients receiving IV midazolam. Midazolam CL was predicted to decrease from 6.7 L/h to 5.1 L/h (24% reduction) when the median population IL-6 concentrations increased from 116 pg/mL to 300 pg/mL.	[12]
Le Carpentier et al., 2022	Retrospective steady-state population PK analysis of midazolam in hospitalized adult COVID-19 patients (n = 48) that received a continuous midazolam infusion while in the ICU. The median OH-midazolam/midazolam ratio was lower in subjects with CRP levels of 50–150 mg/L (66%), 150–250 mg/L (53%) and >250 mg/L (33%) compared to reference subjects with CRP <50 mg/L. The median bound (p < 0.006) or unbound (P < 0.003) OH-midazolam/midazolam ratio was reduced by 20–25% (estimated from figure 4).	[13]
Stader et., 2021	PBPK modeling of the effect of cytokine storm on the metabolism of lopinavir(LPV)/ritonavir and midazolam in COVID-19 infected patients. The PBPK model predicted 2-fold higher LPV exposure in patients with COVID-19 compared to people living with HIV (reference population). The PBPK model predicted 40% higher midazolam exposure in patients with COVID-19 compared to healthy controls.	[10]
Heagler et al., 2021	Retrospective chart analysis of tacrolimus levels in solid organ transplant recipients (n = 55) admitted as inpatients within 14 days of a PCR-positive COVID-19 test. Relative to baseline tacrolimus levels, a clinically significant elevation defined as > 20% in trough tacrolimus levels was observed on admission in 26 (47%) patients. 40 (73%) patients had a clinically significant elevation in trough tacrolimus levels after admission.	[14]
Bajpai et al., 2021	Prospective multicentre analysis of trough tacrolimus levels in adult solid organ transplant recipients (n = 71) within 48 hours of hospital admission for COVID-19. Supratherapeutic trough tacrolimus levels (defined as >7 ng/mL) were observed in 27 (38%) of subjects. Supratherapeutic trough tacrolimus levels were positively associated with the CYP3A5 × 3/*3 poor metabolism genotype, diabetes, baseline proteinuria and use of renin-angiotensin-aldosterone inhibitors.	[15]
Marzolini et al., 2020	Prospective analysis of trough LPV in 92 hospitalized adults with COVID-19 that received LPV/ritonavir and hydroxychloroquine with or without tocilizumab (TCZ). Median trough LPV was higher (30.7 μg/mL vs. 20.9 μg/mL in patients with CRP ≥75 mg/L versus patients (n = 40) with CRP <75 mg/L (n = 52), p < 0.001. Median trough LPV was lower 18.7 μg/mL vs. 28.8 μg/mL in patients receiving TCZ >12 h prior to LPV measure (n = 16) vs. no TCZ or TCZ <12 h prior to LPV measure (n = 76), p < 0.001.	[9]

McColl ER, Croyle MA, Zamboni WC, et al. COVID-19 vaccines and the virus: impact on drug metabolism and pharmacokinetics. Drug Metab Dispos. 2023 Jan;51(1):130–141. doi: 10.1124/dmd.122.000934.

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Rasool SO, Nahr AM, Eskandari S, et al. Drug-disease interactions of differentially expressed genes in COVID-19 liver samples: an in-silico analysis. Investigacion Clinica. 2021;62(4):316–324. doi:10.22209/IC.v62n4a03

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Lenoir C, Terrier J, Gloor Y, et al. Impact of SARS-CoV-2 infection (COVID-19) on cytochromes P450 activity assessed by the Geneva cocktail. Clin Pharmacol Ther. 2021 Nov;110(5):1358–1367. doi: 10.1002/cpt.2412.

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Smeets TJL, Valkenburg AJ, van der Jagt M, et al. Hyperinflammation Reduces midazolam metabolism in critically Ill adults with COVID-19. Clin Pharmacokinet. 2022 Jul;61(7):973–983.

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Le Carpentier EC, Canet E, Masson D, et al. Impact of inflammation on midazolam metabolism in severe COVID-19 patients. Clin Pharmacol Ther. 2022 Nov;112(5):1033–1039.

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Stader F, Battegay M, Sendi P, et al. Physiologically based pharmacokinetic modelling to investigate the impact of the cytokine storm on CYP3A drug pharmacokinetics in COVID-19 patients. Clin Pharmacol Ther. 2022 Mar;111(3):579–584.

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Heagler K, Tejani K, Sanchez S. Impact of Covid-19 infection on tacrolimus levels in solid organ transplant recipients. Am J Transplant. 2021;21(S4): 861.

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Bajpai D, Saxena N, Gandhi C, et al. Does COVID-19 increase tacrolimus levels in kidney transplant recipients? J Clin Pharm Ther. 2022 May;47(5):707–708.

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Marzolini C, Stader F, Stoeckle M, et al. Effect of systemic inflammatory response to SARS-CoV-2 on lopinavir and hydroxychloroquine plasma concentrations. Antimicrob Agents Chemother. 2020 Aug 20;64(9). doi: 10.1128/AAC.01177-20

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