pharmaceutics Article Interactions of Potential Anti-COVID-19 Compounds with Multispecific ABC and OATP Drug Transporters Ágnes Telbisz 1,† , Csilla Ambrus 2,3,† , Orsolya Mózner 1,3 , Edit Szabó 1 , György Várady 1 , Éva Bakos 1 , Balázs Sarkadi 1,4, * and Csilla Özvegy-Laczka 1, *   Citation: Telbisz, Á.; Ambrus, C.; Mózner, O.; Szabó, E.; Várady, G.; Bakos, É.; Sarkadi, B.; Özvegy-Laczka, C. Interactions of Potential Anti- COVID-19 Compounds with Multispecific ABC and OATP Drug Transporters. Pharmaceutics 2021, 13, 81. https://doi.org/10.3390/ pharmaceutics13010081 Received: 21 November 2020 Accepted: 31 December 2020 Published: 9 January 2021 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- ms in published maps and institutio- nal affiliations. Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Institute of Enzymology, ELKH Research Centre for Natural Sciences, Magyar Tudósok krt. 2, 1117 Budapest, Hungary; telbisz.agnes@ttk.hu (Á.T.); mozner.orsolya@ttk.hu (O.M.); szabo.edit@ttk.hu (E.S.); varady.gyorgy@ttk.hu(G.V.); bakos.eva@ttk.hu (É.B.) 2 SOLVO Biotechnology, Irinyi József Street 4-20, 1117 Budapest, Hungary; ambrus@solvo.com 3 Doctoral School of Molecular Medicine, Semmelweis University, T˝ uzoltó u. 37-47, 1094 Budapest, Hungary 4 Department of Biophysics and Radiation Biology, Semmelweis University, T˝ uzoltó u. 37-47, 1094 Budapest, Hungary * Correspondence: sarkadi.balazs@ttk.hu (B.S.); laczka.csilla@ttk.hu (C.Ö.-L.) † These authors contributed equally to this work. Abstract: During the COVID-19 pandemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied with analgesics or non- steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering, or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, in this study, we examined the interactions of the repurposed drugs with the key human multidrug transporters present in the major tissue barriers and strongly affecting the pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine; the antihelmintic ivermectin; and the proposed antiviral compounds ritonavir, lopinavir, favipiravir, and remdesivir with the ABCB1/Pgp, ABCG2/BCRP, and ABCC1/MRP1 exporters, as well as the organic anion- transporting polypeptide (OATP)2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning on the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic. Keywords: anti-COVID-19 agents; repurposed drugs; APP-Binding Cassette (ABC) transporters; OATP transporters; in vitro functional studies 1. Introduction During the COVID-19 pandemic, based on in vitro experimental studies, a number of potential antiviral drugs have been proposed for the clinic. These potential treatments were rapidly brought to the attention of the medical community and the general public by the media, while in many cases, drug evaluation agencies could not properly investigate the pharmacokinetics, potential risks, and benefits. Despite this, clinicians and thousands or even millions of lay people started to compassionately use the advocated off-label compounds. The most notorious example is the wide range off-label use of the antimalarial agents chloroquine and hydroxychloroquine, in some cases together with zinc or the wide- spectrum antibacterial agent azithromycin. Chloroquine (CQ) and the less toxic analog hydroxychloroquine (HCQ) are efficient antimalarial drugs, increasing the endosomal pH in both the parasites and the host cells. HCQ is also clinically used in autoimmune diseases [1]. However, these compounds were previously found to have major toxicities, especially by prolonging the cardiac QT interval or causing hypoglycemia. CQ and HCQ were both reported to be moderate inhibitors of CYP2D6 and the ABCB1/Pgp transporter. Interestingly, azithromycin has a similar toxicity to CQ and HCQ to prolong the QT interval [2]. Pharmaceutics 2021, 13, 81. https://doi.org/10.3390/pharmaceutics13010081 https://www.mdpi.com/journal/pharmaceutics