title: Mechanistic studies of the transdermal iontophoretic delivery of 5-OH-DPAT in vitro.
abstract: A characterization and optimization of the in vitro transdermal iontophoretic transport of 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT) is presented. The utility of acetaminophen as a marker of electroosmotic flow was studied as well. The following parameters of iontophoretic transport of 5-OH-DPAT were examined: drug donor concentration, electroosmotic contribution, influence of co-ions, current density, and composition of the acceptor phase. The steady-state flux (Flux(ss)) of acetaminophen was linearly correlated with the donor concentration and co-iontophoresis of acetaminophen did not influence the iontophoretic flux of 5-OH-DPAT, indicating that acetaminophen is an excellent marker of electroosmotic flow. Lowering the Na(+) concentration from 78 to 10 mM in the donor phase, resulted in a 2.5-fold enhancement of the Flux(ss). The Flux(ss) showed a nonlinear relation with the drug donor concentration and an excellent linear correlation with the current density. Reducing the pH of the acceptor phase from 7.4 to 6.2 resulted in a dramatic decrease of the Flux(ss) of 5-OH-DPAT, explained by a reduced electroosmotic flow and an increased counter-ion flow. Optimization of the conditions resulted in a maximum Flux(ss) of 5-OH-DPAT of 1.0 micromol x cm(-2) h(-1) demonstrating the potential of the iontophoretic delivery of this dopamine agonist for the symptomatic treatment of Parkinson's disease.
authors.affiliation: Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Ackaert
authors.forename: Jeroen
authors.initials: J
authors.lastname: Van Smeden
authors.forename: Jeroen
authors.initials: J
authors.lastname: De Graan
authors.forename: Durk
authors.initials: D
authors.lastname: Dijkstra
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Joke A
authors.initials: JA
authors.lastname: Bouwstra
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000082:Acetaminophen / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000279:Administration, Cutaneous; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D053841:Electroosmosis; D006801:Humans; D066298:In Vitro Techniques; D007478:Iontophoresis; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility
chemical_list: D000978:Antiparkinson Agents; D000082:Acetaminophen; C011799:5-hydroxy-2-N,N-dipropylaminotetralin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin