key: cord-1023274-iau0wdeu
authors: Scherrmann, Jean‐Michel
title: Possible role of ABCB1 in lysosomal accumulation of azithromycin in COVID‐19 therapy
date: 2020-08-17
journal: Clin Pharmacol Ther
DOI: 10.1002/cpt.2020
sha: 0c13acb8fa91511331013a8a6989f7f2216cd164
doc_id: 1023274
cord_uid: iau0wdeu

The antiviral use of azithromycin in COVID‐19 was recently reported by Damle et al. Its combination with hydroxychloroquine did not aim at preventing bacterial super‐infection as often believed, but at benefiting from their common lysosomotropic properties which buffer the acidic conditions (pH 4‐5) of the endolysosomal lumen where SARS‐CoV‐2 transits following its ACE‐2 receptor‐mediated endocytosis. These two powerful cationic and amphiphilic drugs increase up to neutrality the intravesicular pH causing disorders in lysosomal functions such as enzyme inhibitions involved in the virus replication cycle. We recently hypothesized that the ATP‐binding cassette ABCB1 (P‐glycoprotein) could be involved in this reported synergistic effect.

amphiphilic drugs increase up to neutrality the intravesicular pH causing disorders in lysosomal functions such as enzyme inhibitions involved in the virus replication cycle [3] . We recently hypothesized that the ATP-binding cassette ABCB1 (P-glycoprotein) could be involved in this reported synergistic effect [4] . ABCB1 is both expressed on plasma cellular and lysosome/endosome membranes of the lung epithelial cells. Therefore, the substrate transport is directed from the cell cytosol to the extra-cellular fluids at the level of the plasma membrane and to the lumen of lysosomes, respectively. Thus, the intracellular ABCB1 transport could result in increasing the endolysosomal accumulation of ABCB1 substrates.

Damle et al reported that azithromycin is not a sensitive substrate but an inhibitor and that hydroxychloroquine is both a substrate and an inhibitor of ABCB1. On the contrary, several in vitro, in vivo and clinical studies clearly suggest that azithromycin is an ABCB1 substrate, whereas hydroxychloroquine was never characterized as a substrate or an inhibitor with usual in vitro transport assays but assumed as a moderate inhibitor in two human pharmacokinetics which have shown a light increase of the oral bioavailability of two ABCB1 substrates, digoxin and nelfinavir when co-administered with hydroxychloroquine.

These discrepant points of view did not challenge Damle's message that "P-gp efflux would not be expected to be rate-limiting" for the lung distribution because the neutral forms of both drugs have extensive volumes of distribution. Nevertheless, we could raise the question of the role of ABCB1 at the endolysosomal level versus the substrate/inhibitor status of these drugs.

On the one hand, ABCB1 can more extensively enhance the substrate azithromycin trapping as expected by the sole diffusion mechanism [5] . On the other hand, the possible ABCB1 inhibition by hydroxychloroquine could damper this effect. These dual effects on ABCB1 could be further assessed using in vitro cellular models to better clarify the possible interplay between the two drugs and ABCB1.

Thus, we recommend considering ABCB1 at the endolysosomal network for a better understanding of the mechanisms of action of azithromycin when combined with hydroxychloroquine. Since the clinical benefit of this drug combination remains uncertain, further experimental investigations are now needed to determine the role of the endolysosomal ABCB1 in COVID-19 therapy.

This article is protected by copyright. All rights reserved Accepted Article

Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19. Clinical pharmacology and therapeutics

Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells. bioRxiv

Different host cell proteases activate the SARS-coronavirus spike-protein for cell-cell and virus-cell fusion

Intracellular ABCB1 as a possible mechanism to explain the synergistic effect of hydroxychloroquine-azithromycin combination in COVID-19 therapy

Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin

This article is protected by copyright. All rights reserved Accepted Article