Table 1.

Potential GI and liver adverse effects and drug interaction profile of COVID-19 investigational drugs

	Mechanism of action	GI affection	Liver affection	Major drug-drug interactions
Chloroquine/hydroxychloroquine [80]	Interferences with terminal glycosylation of ACE2 receptor Blocks viral entry by increasing endosomal pH and inhibiting viral fusion to the cell membrane	Nausea, vomiting, weight loss, abdominal pain	Rare elevations in aminotransferases. Most reactions are Idiosyncrasy or oxidative stress.	A moderate inhibitor of CYP2D6 and P-gp Significant particularly with anti-rejection immunosuppressants. Weak interaction with tenofovir/entecavir Hydroxychloroquine given to a patient taking hepatitis c treatment should monitor for cardiac arrhythmia
Ivermectin [81]	Inhibition of viral IMPα/β1-mediated nuclear import, which reduces the replication of the virus and so the viral load	Nausea, vomiting, diarrhea	Very few reports on elevated liver enzymes or Jaundice	Avoid concomitant use of ivermectin with other drugs that enhance GABA activity
Nitazoxanide [82]	Antiparasitic drug has broad-spectrum anti-viral activity	Abdominal pain (8%), diarrhea (2%), nausea (3%), vomiting (1%)	Increased ALT: <1%	Rapidly hydrolyzed to tizoxanide. which is highly protein-bound (>99%), so caution when giving with other highly protein-bound drugs with narrow therapeutic indices.
Atazanavir [83]	Protease inhibitors	Diarrhea, nausea, vomiting, abdominal pain	Indirect hyperbilirubinemia with overt jaundice Elevation of hepatic enzymes especially in patients with underlying HBV or HCV co-infection	Inhibitor of CYP3A4 and CYP2C9 PPI decreases its concentrations. Tenofovir and efavirenz should not be co-administered with atazanavir
Favipiravir [84]	RNA-dependent RNA polymerase inhibitor	Nausea/vomiting (5–15%), diarrhea (5%)	Liver enzyme abnormalities	Inhibitor for: CYP2C8 and aldehyde oxidase
Interferon beta [85]	Cytokines with anti-viral and immunomodulatory effects.	Nausea, vomiting	Elevated liver enzymes	DDI potential not fully evaluated. Possible inhibitor of CYP enzymes
Lopinavir/ritonavir [86]	HIV protease inhibitor/CYP450inhibitor	Nausea/vomiting (5–10%), abdominal pain (1–10%), diarrhea (10–30%), dysgeusia (< 2%), increased serum amylase/lipase.	Hepatotoxicity ranges from mild elevations in aminotransferases to acute liver failure. Recovery takes 1–2 mo. Might include drug-cytochrome P-450 interaction	Substrate for: CYP3A4, CYP2D6, P-gp Inducer for: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A1 Inhibitor for: CYP3A4 Increased levels of Immunosuppressive drugs (calcineurin and mTOR inhibitors). Moderate interaction risk with tenofovir with renal functions monitoring. Lopinavir/ ritonavir increase concentrations of hepatitis C treatment.
Remdesivir [87]	RNA-dependent RNA polymerase inhibitor	Nausea, vomiting	Deranged liver enzymes Hepatotoxicity reported; frequency is not yet known.	NA
Ribavirin [88]	Inhibit capping of viral messenger RNA, and the viral RNA-dependent polymerase	Nausea	Hepatotoxicity	NA
Anakinra [89]	IL-1R inhibitor	Rare abdominal pain, nausea, diarrhea	Hepatobiliary disorders: Elevated transaminases, noninfectious hepatitis	No effect on CYP450.
Baricitinib [90]	JAK1 and JAK2 inhibitor Inhibit viral endocytosis	Bowel perforation, nausea, vomiting	Hepatitis B reactivation	Partially metabolized by CYP3A4 and a substrate for OAT3 and P-gp OAT3 inhibitors cause a significant effect on baricitinib exposure
Dexamethasone/ Hydrocortisone [59]	Reduction of IL-8, monocyte chemo-attractant protein-1, and Th1 chemokine IFN-γ-inducible protein-10	Nausea, peptic ulcers	NA	Aspirin can increase the risk of bleeding when used with it
Ruxolitinib [91]	Selective JAK inhibitors	NA	Increased ALT Increased AST	Metabolized by CYP3A4 and CYP2C9. So, it is liable to DDIs with inhibitors or inducers of these enzymes. Ruxolitinib may inhibit BCRP and P-gp, and caution is indicated with co-administering with substrates of these transporters with narrow therapeutic indices.
Sarilumab [92]	IL-6R inhibitor	Few cases of gastrointestinal perforation	Increased ALT	No effect on CYP450
Tocilizumab [93]	IL-6R inhibitor (Curbs cytokine release syndrome)	Bowel perforation, pancreatitis, abdominal pain	Elevated liver enzymes, Reactivation of chronic hepatitis B	No effect on CYP450

ACE angiotensin-converting enzyme, ALT alanine aminotransferase, AST aspartate aminotransferase, BCRP breast cancer resistance protein, COVID-19 coronavirus disease-19, CYP cytochrome P450, DDI drug-drug interaction, GABA γ-aminobutyric acid, GI gastrointestinal, HIV human immunodeficiency virus, IFN interferon, IL interleukin, IMP α/β-mediated nuclear import, JAK Janus kinase, OAT organic anion transporter, P-gp P-glycoprotein, PPI proton pump inhibitor, Th t-helper, TOR target of rapamycin