The Pharmacokinetics and Pharmacological Effect of (S)-5-OH-DPAT Following Controlled Delivery with Transdermal Iontophoresis

作者：Ackaert Oliver W; De Graan Jeroen; Shi Shanna; Vreeken Rob; Della Pasqua Oscar E; Dijkstra Durk; Westerink Ben H; Danhof Meindert; Bouwstra Joke A^*

来源：Journal of Pharmaceutical Sciences, 2011, 100(7): 2996-3009.

DOI：10.1002/jps.22492

• transdermal drug delivery
• pharmacokinetic/pharmacodynamic models
• iontophoresis
• microdialysis
• blood-brain barrier
• controlled delivery
• active transport
• diffusion
• mathematical model
• individualized drug therapy

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.

• 出版日期2011-7