COVID-19 Vaccines and the Virus: Impact on Drug Metabolism and Pharmacokinetics

Abstract

This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12 billion vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amid an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. SIGNIFICANCE STATEMENT: Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver cytochrome P450 metabolism of small molecules, enhanced innate immune system metabolism of complex molecules, and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety, and effectiveness and fetal neurodevelopment.

Fig. 1.

General overview of hepatic CYP regulation by infection and inflammation. NO, nitric oxide; NOS, nitric oxide synthase; INF, interferon.

Fig. 2.

Aggregate illustration of clinical and laboratory findings in a case of delirium developing four days after SARS-CoV-2 vaccination. Laboratory findings relevant to the diagnostic process are illustrated in graphs, the computed tomography scan shows evidence of an unsuspected structural brain abnormality, normal pressure hydrocephalus. PMN, neutrophils; lym, lymphocytes; -3mon, 3 months prior to vaccination baseline; GERD, gastroesophageal reflux disease; pre-vacc, prevaccination.

Fig. 3.

Time course of SARS-CoV-2 infection with respect to severity of disease: virus shedding, inflammatory phase, symptom development and therapies. Note the inflammatory phase lasts approximately 15 days in mild cases and is more amplified and extensive in severe cases suggesting that CYP mediated metabolism could be altered for extensive periods of time even with mild infections. Image source: Hulo et al. (2011).

Fig. 4.

Engagement of integrins by the SARS-CoV-2 spike protein could induce changes in hepatic CYP expression and function. (A) SARS-CoV-2 spike protein facilitates virus entry through engagement of beta integrins and angiotensin converting enzyme 2 (ACE2) receptors. (B) Engagement of integrins through the spike protein stimulates outside in cell signaling pathways that can suppress CYP expression and function. Talin can engage integrins from the cytoplasm and alter CYP through inside out signaling pathways. (C) Suppression of talin in human hepatocytes increases CYP activity suggesting that this protein, which supports SARS-CoV-2 infection, plays a notable role in the regulation of CYP.

Fig. 5.

The Innate immune system is the first line of defense against pathogens, such as viruses. The innate immune system response activates adaptive immune processes through Toll-like receptors (TLRs) and antigen presentation. Innate immune cells recognize and phagocytose pathogens that promote cytokine and antigen presentation to T cells. In addition, these same innate immune cells are directly involved in the identification, uptake, and clearance of complex drugs (e.g., nanoparticles, conjugates, biologics).

Fig. 6.

The relationship between viral load measured by plaque-forming units (PFU) and phagocytic function [mean fluorescence intensity (MFI)] of monocytes in blood of infected mice on day 4 post infection. There is a slight inversion relationship between viral load and phagocytic function. Thus, the amount of viral load may also affect the degree of change in innate immune system function and change in pharmacokinetic and pharmacodynamic disposition of complex drugs.

Fig. 7.

Simulated plasma concentration versus time curves of liposomal encapsulated doxorubicin in mice. Noninfected mice administered a single intravenous dose of PEG-liposomal doxorubicin (6 mg/kg) are shown by the black line. Infected mice administered a single intravenous dose of PEG-liposomal doxorubicin (6 mg/kg) are shown in red. Infected mice administered a single intravenous dose of PEG-liposomal doxorubicin (12 mg/kg) are shown in green.