title: Transdermal delivery of peptides by iontophoresis.
abstract: Transdermal administration by iontophoresis (enhanced transport via the skin using the driving force of an applied electric field) has been successfully demonstrated but no formal relationship between peptide sequence/structure and efficiency of delivery has been established. There are notable examples, such as the lipophilic leutinizing hormone releasing hormone (LHRH) analogs, Nafarelin and Leuprolide, that exhibit down-regulation of their own transport across the skin under the influence of an iontophoretic current. The hypothesis that this phenomenon is due to neutralization of the skin's net negative charge by these cationic peptides was examined with LHRH oligopeptides. The impact of these compounds on the electroosmotic flow of solvent into the skin, which is induced by iontophoresis and which contributes significantly to the electrotransport of large, positively charged ions, was examined and quantified. Close juxtaposition of cationic and lipophilic residues profoundly inhibited electroosmosis and, presumably, peptide flux. The results indicate that the lipophilicity of the oligopeptides facilitates van der Waals interactions with hydrophobic patches along the transport route, thereby permitting the positively charged oligopeptide to interact with carboxylate side chains that give the skin its net negative charge at neutral pH. The lipophilic, cationic oligopeptide, therefore, becomes anchored in the transport path, neutralizing the original charge of the membrane, and completely altering the permselective properties of the skin.
authors.affiliation: Department of Biopharmaceutical Sciences, University of California-San Francisco, CA 94143-0446, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hirvonen
authors.forename: Y N
authors.initials: YN
authors.lastname: Kalia
authors.forename: R H
authors.initials: RH
authors.lastname: Guy
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006728:Hormones / Q000008:administration & dosage / Q000494:pharmacology; D007478:Iontophoresis; D016729:Leuprolide / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008812:Mice, Hairless; D017274:Nafarelin / Q000008:administration & dosage / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009994:Osmolar Concentration; D012869:Skin Absorption; D013329:Structure-Activity Relationship
chemical_list: D018931:Antineoplastic Agents, Hormonal; D006728:Hormones; D009842:Oligopeptides; D017274:Nafarelin; D016729:Leuprolide