Experimental And Conformational Analyses Of Interactions Between Butenafine And Lipids

Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochloride)
is an antifungal agent of the benzylamine class that has excellent therapeutic
efficacy and a remarkably long duration of action when applied topically to treat
various mycoses. Given the lipophilic nature of the molecule, efficacy may be
related to an interaction with cell membrane phospholipids and permeabilization
of the fungal cell wall. Similarly, high lipophilicity could account for the long
duration of action, since fixation to lipids in cutaneous tissues might allow
them to act as local depots for slow release of the drug. We have therefore used
computer-assisted conformational analysis to investigate the interaction of
butenafine with lipids and extended these observations with experimental studies
in vitro using liposomes. Conformational analysis of mixed monolayers of
phospholipids with the neutral and protonated forms of butenafine highlighted a
possible interaction with both the hydrophilic and hydrophobic domains of
membrane phospholipids. Studies using liposomes demonstrated that butenafine
increases membrane fluidity [assessed by fluorescence polarization of
1-(4-trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene and
1,6-diphenylhexatriene] and membrane permeability (studied by release of calcein
from liposomes). The results show, therefore, that butenafine readily interacts
with lipids and is incorporated into membrane phospholipids. These findings may
help explain the excellent antifungal efficacy and long duration of action of
this drug when it is used as a topical antifungal agent in humans.