Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
Autor: | Éva Bakos, Ágnes Telbisz, Csilla Özvegy-Laczka, Csilla Ambrus, Balázs Sarkadi |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Cell biology
SLC47A1 Organic Cation Transport Proteins Science Diseases Comorbidity Pharmacology Antiviral Agents Lopinavir Article Substrate Specificity medicine Humans ATP Binding Cassette Transporter Subfamily B Member 11 SLC10A1 Alanine Ritonavir Multidisciplinary Organic cation transport proteins biology Liver-Specific Organic Anion Transporter 1 SARS-CoV-2 Drug discovery Chemistry Multidrug resistance-associated protein 2 Drug Repositioning Transporter Adenosine Monophosphate Multidrug Resistance-Associated Protein 2 COVID-19 Drug Treatment Liver biology.protein Medicine Drug metabolism medicine.drug |
Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-10 (2021) Scientific Reports |
ISSN: | 2045-2322 |
Popis: | 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. |
Databáze: | OpenAIRE |
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