Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters

In the COVID-19 epidemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied together 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, here we examined the interactions of the repurposed drugs with the key human multidrug transporters, present in the major tissue barriers and strongly affecting 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 OATP2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning for the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.