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 th...

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Autores principales:	Csilla Ambrus, Éva Bakos, Balázs Sarkadi, Csilla Özvegy-Laczka, Ágnes Telbisz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4ddf4cfaa6b9472a9a671a89aa7c8a37
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spelling	oai:doaj.org-article:4ddf4cfaa6b9472a9a671a89aa7c8a372021-12-02T14:58:48ZInteractions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics10.1038/s41598-021-97160-32045-2322https://doaj.org/article/4ddf4cfaa6b9472a9a671a89aa7c8a372021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97160-3https://doaj.org/toc/2045-2322Abstract 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.Csilla AmbrusÉva BakosBalázs SarkadiCsilla Özvegy-LaczkaÁgnes TelbiszNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Csilla Ambrus Éva Bakos Balázs Sarkadi Csilla Özvegy-Laczka Ágnes Telbisz Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
description	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.
format	article
author	Csilla Ambrus Éva Bakos Balázs Sarkadi Csilla Özvegy-Laczka Ágnes Telbisz
author_facet	Csilla Ambrus Éva Bakos Balázs Sarkadi Csilla Özvegy-Laczka Ágnes Telbisz
author_sort	Csilla Ambrus
title	Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
title_short	Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
title_full	Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
title_fullStr	Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
title_full_unstemmed	Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
title_sort	interactions of anti-covid-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4ddf4cfaa6b9472a9a671a89aa7c8a37
work_keys_str_mv	AT csillaambrus interactionsofanticovid19drugcandidateswithhepatictransportersmaycauselivertoxicityandaffectpharmacokinetics AT evabakos interactionsofanticovid19drugcandidateswithhepatictransportersmaycauselivertoxicityandaffectpharmacokinetics AT balazssarkadi interactionsofanticovid19drugcandidateswithhepatictransportersmaycauselivertoxicityandaffectpharmacokinetics AT csillaozvegylaczka interactionsofanticovid19drugcandidateswithhepatictransportersmaycauselivertoxicityandaffectpharmacokinetics AT agnestelbisz interactionsofanticovid19drugcandidateswithhepatictransportersmaycauselivertoxicityandaffectpharmacokinetics
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Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics

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