Transdermal iontophoretic delivery of a novel series of dopamine agonists in vitro: physicochemical considerations.
OBJECTIVE
The transdermal iontophoretic delivery of a novel series of 2- aminotetralins and chromanamine-based dopamine agonists was investigated in vitro.


METHODS
Systematic structural modifications allowed us to investigate their effect on solubility in the donor phase and iontophoretic delivery across human skin. Transport profiles were analysed with nonlinear mixed effect modelling, utilizing an extension to an existing compartmental model. Furthermore, relationships between physicochemical properties and transport parameters were addressed.


RESULTS
A solubility increase was observed: 5,6-di-OH-DPAT < 5-OH-MPAT < 5-OH-EPAT < 8-OH-DPAC. The structure significantly affected the iontophoretic delivery across human stratum corneum and dermatomed human skin with the highest flux for 5-OH-EPAT and 5-OH-MPAT. The extended model with two skin release constants (K(R1), K(R2)) described more adequately iontophoretic transport profiles than the existing model with one release constant. The extended model suggested two parallel transport pathways during current application. Across human stratum corneum, the electrophoretic mobility, measured with capillary electrophoresis, showed a linear relationship with the electromigrative flux and the zero-order iontophoretic mass input into the skin (I(0)).


CONCLUSIONS
Combining transport parameters (I(0), K(R1) and K(R2)), predicted from physicochemical properties, with compartmental modelling provided a powerful tool to simulate iontophoretic transport profiles for screening potential candidates and designing experiments.
Ackaert
Oliver W
OW
Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Leiden, the Netherlands.
De Graan
Jeroen
J
Capancioni
Romano
R
Dijkstra
Durk
D
Danhof
Meindert
M
Bouwstra
Joke A
JA
D001692:Biological Transport; D002839:Chromans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D015195:Drug Design; D019075:Electrophoresis, Capillary; D006801:Humans; D007478:Iontophoresis; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012869:Skin Absorption; D012995:Solubility; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
D002839:Chromans; D018491:Dopamine Agonists; D013764:Tetrahydronaphthalenes; C006561:2-aminotetralin