Ublic; [email protected] Correspondence: [email protected]: Huli iak, M.; Vok , I.; c r Holas, O.; Martinec, O.; Staud, F.; Cerven L. Evaluation of the Potency of Anti-HIV and Anti-HCV Drugs to Inhibit P-Glycoprotein Mediated Efflux of Digoxin in Caco-2 Cell Line and Human Precision-Cut Intestinal Slices. Pharmaceuticals 2022, 15, 242. doi.org/10.3390/ph15020242 Academic Editor: Juan Carlos Saiz Received: 11 January 2022 Accepted: 15 February 2022 Published: 18 February 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Abstract: The inhibition of P-glycoprotein (ABCB1) could lead to improved drug plasma concentrations and hence boost drug toxicity. The evaluation of a drug’s capacity to inhibit ABCB1 is complicated by the presence of various transport-competent websites inside the ABCB1 binding pocket, making it tricky to choose suitable substrates. Here, we investigate the capacity of antiretrovirals and direct-acting antivirals to inhibit the ABCB1-mediated intestinal efflux of [3 H]-digoxin and evaluate it with our previous rhodamine123 study. At concentrations of up to one hundred , asunaprevir, atazanavir, daclatasvir, darunavir, elbasvir, etravirine, grazoprevir, ledipasvir, lopinavir, rilpivirine, ritonavir, saquinavir, and velpatasvir inhibited [3 H]-digoxin transport in Caco-2 cells and/or in precision-cut intestinal slices prepared in the human jejunum (hPCIS).P-selectin, Human (HEK293, His) Having said that, abacavir, dolutegravir, maraviroc, sofosbuvir, tenofovir disoproxil fumarate, and zidovudine had no inhibitory impact.DKK-3 Protein Source We therefore found that most of the tested antivirals possess a higher possible to result in drug rug interactions on intestinal ABCB1.PMID:23613863 Comparing the Caco-2 and hPCIS experimental models, we conclude that the Caco-2 transport assay is far more sensitive, but the benefits obtained working with hPCIS agree improved with reported in vivo observations. Far more inhibitors have been identified when making use of digoxin because the ABCB1 probe substrate than when using rhodamine123. Having said that, each approaches had limitations, indicating that inhibitory potency should really be tested with no less than these two ABCB1 probes. Keyword phrases: drug rug interactions; ABCB1; antiretrovirals; direct-acting antivirals; human precisioncut intestinal slices1. Introduction Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections are big international well being challenges. More than 100 million individuals are at the moment living with HIV or HCV [1], nearly 30 million of whom have already been prescribed a lifelong antiretroviral combination regimen or months of medication with combinations of direct-acting antivirals (DAA) [1,2]. Sufferers with HIV and/or HCV regularly have significant comorbidities that demand the administration of added pharmacotherapy [40], which increases the threat of drug rug interactions (DDI) [114]. While antivirals are very efficient and well tolerated, they share metabolic pathways with other drugs and reveal frequent interactions with membrane transporters. This creates the prospective for pharmacokinetic DDI that could result in a victim drug’s plasma concentration to attain toxic or subtherapeutic levels [11,15]. For that reason, know-how in the molecular mechanisms underpinning pharmacokinetic DDI is essential for choosing proper antivirals and optimal antiviral doses [11,15]. Most antivirals are thought to be substrates and/or inhibitors of P-glycoprotein (ABCB1) [168]. ABCB1 is definitely an active efflux transporter that determ.