The in vitro and in vivo evaluation of new synthesized prodrugs of 5-OH-DPAT for iontophoretic delivery

The feasibility of transdermal iontophoretic transport of 4 novel ester prodrugs of 5-OH-DPAT (glycine-, proline-, valine- and β-alanine-5-OH-DPAT) was investigated in vitro and in vivo. Based on the chemical stability of the prodrugs, the best candidates were selected for in vitro transport studies across human skin. The pharmacokinetics and pharmacodynamic effects of the prodrug with highest transport efficiency, were investigated in a rat model. The in vitro transport, plasma profile and pharmacological response were analyzed with compartmental modeling. Valine- and β-alanine-5-OH-DPAT were acceptably stable in the donor phase and showed a 4-fold and 14-fold increase in solubility compared to 5-OH-DPAT. Compared to 5-OH-DPAT, valine- and β-alanine-5-OH-DPAT were transported less and more efficiently across human skin, respectively. Despite a higher in vitro transport, lower plasma concentration was observed following 1.5 h current application (250 μA cm2) of β-alanine-S-5-OH-DPAT in comparison to S-5-OH-DPAT. However the prodrug showed higher plasma concentrations post-iontophoresis, explained by a delayed release due to hydrolysis and skin depot formation. This resulted in a pharmacological effect with the same maximum as 5-OH-DPAT, but the effect lasted for a longer time. The current findings suggest that β-alanine-5-OH-DPAT is a promising prodrug, with a good balance between stability, transport efficiency and enzymatic conversion.

Figure optionsDownload as PowerPoint slideThe plasma profile (Panel A + B) and pharmacodynamic effect (panel C) following transdermal iontophoretic delivery of the prodrug β-ala-S-5-OH-DPAT (open circle) and the parent drug S-5-OH-DPAT(closed triangle).