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.
Highlights
During the COVID-19 pandemic, based on in vitro experimental studies, a number of potential antiviral drugs have been proposed for the clinic
Based on both in vitro and clinical data, OATP1A2 and OATP2B1 are key players in the intestinal uptake of a large variety of clinically important drugs, including statins, fexofenadine, sulfasalazine, steroids, and telmisartan, while they may be significantly inhibited by chemotherapeutics or antiviral compounds [42]. They contribute to the tissue penetration of numerous endogenous substrates, including steroid and thyroid hormones, prostaglandins, bile acids, and bilirubin [43]. Based on their important role in tissue barriers and drug pharmacokinetics, we studied the potential inhibition of the function of ABCB1, ABCG2, ABCC1, OATP2B1, and OATP1A2 by the clinically applied anti-COVID-19 agents
The cellular uptake of the non-fluorescent CaAM is strongly inhibited by the extrusion of this compound by the ABCB1 transporter, so the cellular fluorescence of the intracellularly formed free Calcein is strongly reduced in cells expressing ABCB1 [53]
Summary
During the COVID-19 pandemic, based on in vitro experimental studies, a number of potential antiviral drugs have been proposed for the clinic. Based on both in vitro and clinical data, OATP1A2 and OATP2B1 are key players in the intestinal uptake of a large variety of clinically important drugs, including statins, fexofenadine, sulfasalazine, steroids, and telmisartan, while they may be significantly inhibited by chemotherapeutics or antiviral compounds [42] They contribute to the tissue penetration of numerous endogenous substrates, including steroid and thyroid hormones, prostaglandins, bile acids, and bilirubin [43]. Based on their important role in tissue barriers and drug pharmacokinetics, we studied the potential inhibition of the function of ABCB1, ABCG2, ABCC1, OATP2B1, and OATP1A2 by the clinically applied anti-COVID-19 agents. We used an array of in vitro functional transporter assays which, together, may provide important new information regarding the potential ADME-tox properties of these agents
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