RESUMO
The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the active (S)-enantiomer of the potent dopamine (DA) agonist 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT) were investigated in a novel anesthetized animal model. First, the relationship between current density, in vivo transport, and plasma profile was characterized. Second, the effect of the anesthetic mixture, transdermal iontophoresis, and blood sampling on the striatal DA release (PD end point) was investigated. Third, the PK-PD relationship following transdermal iontophoresis was investigated during a controlled reversible pharmacological response. Given that striatal DA levels are unaltered during experimental procedures, this rat model can be used to investigate the PK-PD relationship. The in vivo flux was linearly correlated with the current density, indicating that drug delivery can be titrated by the current density. Following transdermal iontophoresis and intravenous infusion, a strong reversible effect was observed. Compartmental modeling showed that the relationship between plasma concentration and biomarker response is best characterized by an effect compartment, rather than an indirect response model. In addition, covariate analysis suggested that the delivery rate can affect the PD efficiency. Finally, PK-PD analysis revealed that steady delivery rates are translated into continuous dopaminergic stimulation. This can be of benefit for reducing side effects in the symptomatic treatment of Parkinson's disease with 5-OH-DPAT.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/análogos & derivados , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Gânglios da Base/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacocinética , Iontoforese , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/sangue , 8-Hidroxi-2-(di-n-propilamino)tetralina/química , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacocinética , Administração Cutânea , Anestésicos Inalatórios/farmacologia , Animais , Antiparkinsonianos/sangue , Antiparkinsonianos/química , Gânglios da Base/metabolismo , Preparações de Ação Retardada , Difusão , Dopamina/metabolismo , Agonistas de Dopamina/sangue , Agonistas de Dopamina/química , Infusões Intravenosas , Isoflurano/farmacologia , Masculino , Microdiálise , Modelos Biológicos , Dinâmica não Linear , Ratos , Ratos WistarRESUMO
OBJECTIVES: 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. KEY FINDINGS: 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.
Assuntos
Cromanos/farmacocinética , Agonistas de Dopamina/farmacocinética , Absorção Cutânea , Tetra-Hidronaftalenos/farmacocinética , Transporte Biológico , Cromanos/administração & dosagem , Cromanos/química , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/química , Desenho de Fármacos , Eletroforese Capilar , Humanos , Iontoforese , Modelos Biológicos , Dinâmica não Linear , Solubilidade , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/químicaRESUMO
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.