1: Eur J Pharmacol 1996 Oct 24;314(1-2):215-27
Interaction of the macrolide azithromycin with phospholipids. II. Biophysical
and computer-aided conformational studies.
Montenez JP, Van Bambeke F, Piret J, Schanck A, Brasseur R, Tulkens PM,
Mingeot-Leclercq MP
Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique
de Louvain, UCL 73.70, Bruxelles, Belgium.
In a comparison paper, we show the azithromycin causes a lysosomal phospholipidosis
in cultured cells, binds in vitro to negatively charged bilayers without
causing aggregation or fusion, and inhibits lysosomal phospholipase A1.
In this paper, we show that azithromycin decreases the mobility of the
phospholipids in negatively charged liposomes (using 31P nuclear magnetic
resonance) and that it increases the fluidity of the acyl chains close
to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic
domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene
and diphenyhexatriene, respectively). Computer-aided conformational
analysis of mixed monolayers of azithromycin and phosphatidylinositol shows
that the drug can be positioned largely in thehydrophobic domain, but close
to the interface, with the macrocycle facing the C1 of the fatty acids
(allowing the N9a endocyclic tertiary amine to interact with the phospho-groups),
the cladinose located on the hydrophobic side of the lipid/water interface
and the desosamine projected into the hydrophobic domain. This position
is consistent with the experimental data. Analysis of virtual molecules
shows that this unanticipated behavior to the shielding of the ionizable
N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion
of hydrophobic domains all over the molecule. The interaction of azithromycin
with phospholipids may account for some of its unusual pharmacokinetic
properties and for its potential to cause lysosomal phospholipidosis.
PMID: 8957239, UI: 97116151