title: Preclinical investigation of the topical administration of phenserine: transdermal flux, cholinesterase inhibition, and cognitive efficacy.
abstract: Phenserine (PS) was designed as a selective acetylcholinesterase (AChE) inhibitor, with a tartrate form (PST) for oral administration in mild to moderate Alzheimer's disease (AD). Recent phase 3 trials of PST in Europe indicate that any clinically relevant activity of PST may be limited by its duration of action. Like many oral drugs, bioavailability and plasma concentrations of PST are regulated by hepatic and gastrointestinal first-pass effects. To minimize the kinetic limitations of first-pass metabolism, transdermal formulations of PS and PST (ointment/patch) were developed and characterized in vitro and in vivo. Initial in vitro kinetic characterization of PS or PST formulations used a diffusion cell chamber and skin samples isolated from hairless mice. Liquid paraffin and fatty alcohol/propylene glycol (FAPG) were found to be suitable vehicles for ointment formulation. Addition of a penetration enhancer, 1-[2-(decylthio)ethyl]-azacyclopentane-2-one (HPE-101), improved stratum corneum permeability. Application of the optimal formulation of PS/HPE-101/FAPG to the shaved back of rats resulted in significantly lowered plasma and brain AChE activities and improved cognitive performance in animals with scopolamine-induced cognitive impairment. These results suggest that the transdermal application of AChE inhibitors may represent an effective therapeutic strategy for AD. Particular benefits over oral therapies might include avoiding first-pass metabolic effects and improved dosing compliance.
authors.affiliation: Drug Design and Development Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Utsuki
authors.forename: Nao
authors.initials: N
authors.lastname: Uchimura
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Irikura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moriuchi
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Edward L
authors.initials: EL
authors.lastname: Spangler
authors.forename: Jacek
authors.initials: J
authors.lastname: Mamczarz
authors.forename: Donald K
authors.initials: DK
authors.lastname: Ingram
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism*; D000279:Administration, Cutaneous; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D002626:Chemistry, Pharmaceutical; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D015194:Diffusion Chambers, Culture; D004597:Electroshock; D005079:Excipients; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009824:Ointments; D010830:Physostigmine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012601:Scopolamine / Q000494:pharmacology; D012869:Skin Absorption / Q000187:drug effects*
chemical_list: D002800:Cholinesterase Inhibitors; D005079:Excipients; D018727:Muscarinic Antagonists; D009824:Ointments; D010830:Physostigmine; D012601:Scopolamine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C092280:phenserine