Experimental and conformational analyses of interactions between butenafine and lipids

Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochlo ride) is an antifungal agent of the benzylamine class that has excellent th erapeutic efficacy and a remarkably long duration of action when applied to pically to treat various mycoses. Given the lipophilic nature of the molecu le, efficacy may be related to an interaction with cell membrane phospholip ids and permeabilization of the fungal cell wall. Similarly, high lipophili city could account for the long duration of action, since fixation to lipid s in cutaneous tissues might allow them to act as local depots for slow rel ease of the drug. We have therefore used computer-assisted conformational a nalysis to investigate the interaction of butenafine with lipids and extend ed these observations with experimental studies in vitro using liposomes. C onformational analysis of mixed monolayers of phospholipids with the neutra l and protonated forms of butenafine highlighted a possible interaction wit h both the hydrophilic and hydrophobic domains of membrane phospholipids. S tudies using liposomes demonstrated that butenafine increases membrane flui dity [assessed by fluorescence polarization of 1-(4-trimethylammonium-pheny l)-6-phenyl-1,3,5-hexatriene and 1,6-diphenylhexatriene] and membrane perme ability (studied by release of calcein from liposomes). The results show, t herefore, 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 us ed as a topical antifungal agent in humans.