Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics.

Transporters in the human liver play a major role in the clearance of endo- and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake of, or expel, various compounds from/into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the key drug transporters of hepatocytes. These transporters included ABCB11/BSEP, ABCC2/MRP2, and SLC47A1/MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, SLC22A1/OCT1, SLCO1B1/OATP1B1, SLCO1B3/OATP1B3, and SLC10A1/NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited BSEP and MATE1 exporters, as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the various interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.

Pharmacogenetics Approach for the Improvement of COVID-19 Treatment.

The treatment of coronavirus disease 2019 (COVID-19) has been a challenge. The efficacy of several drugs has been evaluated and variability in drug response has been observed. Pharmacogenetics could explain this variation and improve patients' outcomes with this complex disease; nevertheless, several disease-related issues must be carefully reviewed in the pharmacogenetic study of COVID-19 treatment. We aimed to describe the pharmacogenetic variants reported for drugs used for COVID-19 treatment (remdesivir, oseltamivir, lopinavir, ritonavir, azithromycin, chloroquine, hydroxychloroquine, ivermectin, and dexamethasone). In addition, other factors relevant to the design of pharmacogenetic studies were mentioned. Variants in CYP3A4, CYP3A5, CYP2C8, CY2D6, ABCB1, ABCC2, and SLCO1B1, among other variants, could be included in pharmacogenetic studies of COVID-19 treatment. Besides, nongenetic factors such as drug-drug interactions and inflammation should be considered in the search for personalized therapy of COVID-19.

Pharmacogenomics and COVID-19: clinical implications of human genome interactions with repurposed drugs.

The outbreak of Coronavirus disease 2019 (COVID-19) has evolved into an emergent global pandemic. Many drugs without established efficacy are being used to treat COVID-19 patients either as an offlabel/compassionate use or as a clinical trial. Although drug repurposing is an attractive approach with reduced time and cost, there is a need to make predictions on success before the start of therapy. For the optimum use of these repurposed drugs, many factors should be considered such as drug-gene or dug-drug interactions, drug toxicity, and patient co-morbidity. There is limited data on the pharmacogenomics of these agents and this may constitute an obstacle for successful COVID-19 therapy. This article reviewed the available human genome interactions with some promising repurposed drugs for COVID-19 management. These drugs include chloroquine (CQ), hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir (LPV/r), atazanavir (ATV), favipiravir (FVP), nevirapine (NVP), efavirenz (EFV), oseltamivir, remdesivir, anakinra, tocilizumab (TCZ), eculizumab, heme oxygenase 1 (HO-1) regulators, renin-angiotensin-aldosterone system (RAAS) inhibitors, ivermectin, and nitazoxanide. Drug-gene variant pairs that may alter the therapeutic outcomes in COVID-19 patients are presented. The major drug variant pairs that associated with variations in clinical efficacy include CQ/HCQ (CYP2C8, CYP2D6, ACE2, and HO-1); azithromycin (ABCB1); LPV/r (SLCO1B1, ABCB1, ABCC2 and CYP3A); NVP (ABCC10); oseltamivir (CES1 and ABCB1); remdesivir (CYP2C8, CYP2D6, CYP3A4, and OATP1B1); anakinra (IL-1a); and TCZ (IL6R and FCGR3A). The major drug variant pairs that associated with variations in adverse effects include CQ/HCQ (G6PD; hemolysis and ABCA4; retinopathy), ATV (MDR1 and UGT1A1*28; hyperbilirubinemia; and APOA5; dyslipidemia), NVP (HLA-DRB1*01, HLA-B*3505 and CYP2B6; skin rash and MDR1; hepatotoxicity), and EFV (CYP2B6; depression and suicidal tendencies).