Interaction of Remdesivir with Clinically Relevant Hepatic Drug Uptake Transporters

Anne T Nies,Martin F Fromm,Charlotte Kölz,Ute Hofmann,Jörg König,Matthias Schwab

doi:10.3390/pharmaceutics13030369

Abstract

Remdesivir has been approved for treatment of COVID-19 and shortens the time to recovery in hospitalized patients. Drug transporters removing remdesivir from the circulation may reduce efficacy of treatment by lowering its plasma levels. Information on the interaction of remdesivir with drug transporters is limited. We therefore assessed remdesivir as substrate and inhibitor of the clinically relevant hepatic drug uptake transporters organic anion transporting poly-peptide (OATP)-1B1 (SLCO1B1), its common genetic variants OATP1B1*1b, OATP1B1*5, OATP1B1*15, as well as OATP1B3 (SLCO1B3), OATP2B1 (SLCO2B1) and organic cation transporter (OCT)-1 (SLC22A1). Previously established transporter-overexpressing cells were used to measure (i) cellular remdesivir uptake and (ii) cellular uptake of transporter probe substrates in the presence of remdesivir. There was a high remdesivir uptake into vector-transfected control cells. Moderate, but statistically significant higher uptake was detected only for OATP1B1-, OATP1B1*1b and OATP1B1*15-expressing cells when compared with control cells at 5 µM. Remdesivir inhibited all investigated transporters at 10 µM and above. In conclusion, the low uptake rates suggest that OATP1B1 and its genetic variants, OATP1B3, OATP2B1 and OCT1 are not relevant for hepatocellular uptake of remdesivir in humans. Due to the rapid clearance of remdesivir, no clinically relevant transporter-mediated drug-drug interactions are expected.

Highlights

Remdesivir is a small molecule nucleoside analog inhibitor developed for treating diseases caused by RNA viruses such as Ebola virus [1]
Significant uptake was only detected for OATP1B1
As membrane transporters are known to mediate hepatocellular drug uptake, it was the goal of this in vitro study to investigate whether the major hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and OCT1 are involved in remdesivir uptake

Summary

Introduction

Remdesivir is a small molecule nucleoside analog inhibitor developed for treating diseases caused by RNA viruses such as Ebola virus [1]. As remdesivir effectively inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro and in preclinical animal models of coronavirus disease 2019 (COVID-19), it was evaluated in several clinical trials [2]. Remdesivir (Veklury) is the first Food and Drug Administration (FDA)-approved anti-viral agent to treat hospitalized COVID-19 patients [3,4]. It is a phosphoramidate prodrug that needs to be converted by esterases, phosphoramidases and kinases into its active nucleoside triphosphate analog inhibiting viral RNA-dependent. Pharmaceutics 2021, 13, 369 a considerable uptake into the liver. It is important to investigate molecular mechanisms of hepatocellular remdesivir uptake

Objectives

Methods

Results

Conclusion