Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy
Scherrmann,
Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of..,
, AAPS J 22, 86 (2020), doi:10.1208/s12248-020-00465-w (Theory)
Proposes a new mechanism supporting the synergistic interaction between HCQ+AZ.
Scherrmann et al., 12 Jun 2020, peer-reviewed, 1 author.
Abstract: The AAPS Journal
(2020) 22:86
DOI: 10.1208/s12248-020-00465-w
Commentary
Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect
of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy
JM. Scherrmann1,2,3
Received 17 April 2020; accepted 19 May 2020
Abstract.
The co-administration of hydroxychloroquine with azithromycin is proposed in
COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction
between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is
localized in endosomes and lysosomes with a polarized substrate transport from the cell
cytosol into the vesicle interior. SARS-CoV-2 and drugs meet in these acidic organelles and
both basic drugs, which are potent lysosomotropic compounds, will become protonated and
trapped within these vesicles. Consequently, their intra-vesicular concentrations can attain
low micromolar effective cytotoxic concentrations on SARS-CoV-2 while concomitantly
increase the intra-vesicular pH up to around neutrality. This last effect inhibits lysosomal
enzyme activities responsible in virus entry and replication cycle. Based on these
considerations, we hypothesize that ABCB1 could be a possible enhancer by confining
azithromycin more extensively than expected when the trapping is solely dependent on the
passive diffusion. This additional mechanism may therefore explain the synergistic effect
when azithromycin is added to hydroxychloroquine, leading to apparently more rapid virus
clearance and better clinical benefit, when compared to monotherapy with
hydroxychloroquine alone.
KEY WORDS: azithromycin; hydroxychloroquine; ABCB1; lysosomes; COVID-19.
The co-administration of the antimalarial chloroquine or
the anti-rheumatic hydroxychloroquine with the antibacterial
azithromycin is presently proposed as a therapy amidst the
COVID-19 pandemic (1). These aminoquinoline drugs and
azithromycin are being repurposed for their clinical use in
COVID-19, and they should be evaluated according to
current practices of drug clinical trials for this indication.
Although this process is normally time-consuming, population, media, and political pressures have propelled the use of
this combined therapy on an emergency basis, thus opening
controversial pro and con debates. Moreover, most of the
different aminoquinoline clinical trials over the world are not
comparable as they differ in terms of mono or bi-therapy
choice, dosage regimen, and optimal time of administration
versus the disease time course and severity. Several Chinese
clinical trials have been based on the sole chloroquine or
hydroxychloroquine administration and their clinical efficacies remain uncertain (2–4). Additionally, most of these
methodological protocols suffer from major concerns in term
1
Faculty of Pharmacy, University of Paris, Inserm UMRS-1144, Paris,
France.
2
Laboratoire de Pharmacocinétique, Faculté de Pharmacie, 4, avenue
de l’Observatoire, 75006, Paris, France.
3
To whom correspondence should be addressed. (e–mail: jeanmichel.scherrmann@inserm.fr)
of trial design quality such as inappropriateness in randomization, patient population size, and other limiting factors
(5,6). The purpose of this commentary is to discuss the
possible rationale for co-administering the antibiotic
azithromycin with hydroxychloroquine, recognizing that
azithromycin is not being used for its antibacterial activity
but for its additive or synergistic effect on the antiviral action
of..
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