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

Abstract

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.

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection

“…Yet, the idea of its use has not generated any desirable interest at the governmental or pharmaceutical level. Meanwhile, numerous potentially toxic and expensive repurposed drugs have been espoused or used as clinical treatments, e.g., colchicine [19], glucocorticoids [20], remdesivir [14,21], and many others [22][23][24][25]. Although of significant value, even the currently available vaccines are not without occasional serious side effects [26][27][28].…”

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro

“…The differential impact of remdesivir could be due to different treatment periods (Akinci et al 2020 ; Choi et al 2020 ; Xu et al 2020 ), cell types and experimental readouts. In particular, the expression patterns/levels of cellular transporters for remdesivir or its metabolites may alter among cell types and thus their sensitivity for remdesivir-induced adverse effects (Akinci et al 2020 ; Ambrus et al 2021 ; Miller et al 2021 ; Nies et al 2021 ; Telbisz et al 2021 ). For example, Xu et al ( 2020 ) tested several cell types and the only cell line with clear mitochondrial toxicity (PC-3) was the one with the highest intracellular amount of remdesivir triphosphate (RTP), the active metabolite of remdesivir.…”

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

“…Transporter inhibitors are compounds that competitively bind or inhibit transporter activity [ 23 , 24 ]. Therefore, in the case of multi-disease combination, there will be interactions between drugs, such as P-gp [ 25 , 26 ], which has a variety of inducers in vivo, including antibacterial drug rifampicin, anti-tumor drug vincristine, doxorubicin, cardiovascular drug verapamil [ 27 ], hyperlipidemia drug atorvastatin [ 28 ], etc., which can induce the overexpression of P-gp in vivo. As a result, the pharmacokinetics parameters of drugs such as digoxin in vivo are significantly changed, while digoxin has a narrow treatment window, and the blood concentration of digoxin will be greatly reduced in a multi-drug combination, so that digoxin cannot play a therapeutic role.…”