Table 1 Potential GI and liver adverse effects and drug interaction profile of COVID-19 investigational drugs
| Â | 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 |