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Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin
Discusses pharmacokinetic properties of HCQ+AZ as a potential underlying mechanism of the observed antiviral effects.
Derendorf et al., 7 May 2020, peer-reviewed, 1 author.
Abstract: International Journal of Antimicrobial Agents 55 (2020) 106007
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents
journal homepage: www.elsevier.com/locate/ijantimicag
Excessive lysosomal ion-trapping of hydroxychloroquine and
University of Florida
a r t i c l e
i n f o
Received 22 March 2020
Accepted 28 April 2020
Editor: Jean-Marc Rolain
a b s t r a c t
A recent report identiﬁed signiﬁcant reductions or disappearance of viral load in COVID-19 patients given
a combination of hydroxychloroquine and azithromycin. The present communication discusses some common pharmacokinetic properties of these two drugs that may be linked to a potential underlying mechanism of action for these antiviral effects. The physicochemical properties of both hydroxychloroquine and
azithromycin are consistent with particularly high aﬃnity for the intracellular lysosomal space, which
has been implicated as a target site for antiviral activity. The properties of both drugs predict dramatic
accumulation in lysosomes, with calculated lysosomal drug concentrations that exceed cytosolic and extracellular concentrations by more than 50 0 0 0-fold. These predictions are consistent with previously
reported experimentally measured cellular and extracellular concentrations of azithromycin. This is also
reﬂected in the very large volumes of distribution of these drugs, which are among the highest of all
drugs currently in use. The combination of hydroxychloroquine and azithromycin produces very high
local concentrations in lysosomes. The clinical signiﬁcance of this observation is unclear; however, the
magnitude of this mechanism of drug accumulation via ion-trapping in lysosomes could be an important
factor for the pharmacodynamic effects of this drug combination.
© 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
Recent reports identiﬁed signiﬁcant reduction or disappearance
of viral load in COVID-19 patients given a combination of hydroxychloroquine and azithromycin [1,2]. However, other clinical studies
could not conﬁrm these early ﬁndings  and there are considerable concerns about the safety of this drug combination . The
present communication discusses some common pharmacokinetic
properties of these two drugs that may be linked to a potential
underlying mechanism of action for their pharmacological activity.
1. Chemical structures
Fig. 1 shows the chemical structures of hydroxychloroquine and
azithromycin. Although the two compounds are from two chemically distinct classes, they have a structural similarity that is pharmacokinetically relevant. Both compounds are multibasic amines
with pKa values that are susceptible to protonation in the physiological pH range. Azithromycin has two nitrogens with pKa values of 8.1 and 8.8 . Hydroxychloroquine has three nitrogens with
pKa values of 4.0, 8.3 and 9.7 . However, only the two nitrogens
with the higher values (shown in circles in Fig. 1) are protonated
under physiological conditions.
E-mail address: hartmut@uﬂ.edu
2. Lysosomal ion-trapping
If the pH of the molecular environment is lower (more acidic),
more nitrogens are protonated, which in turn hinders the nowcharged moieties from crossing membranes. This is particularly relevant for the intracellular distribution of basic drugs crossing between the cytosol (pH approx. 7.4) and the acidic lysosomal space
(pH approx. 5.0). Fig. 2..
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