Physicochemical properties and transport behaviour of piribedil: Considerations on its membrane-crossing potential

The lipophilicity (expressed by log P_oct) and H-bond donor acidity (expressed by Δ log P_oct-hep) of the dopaminergic agonist piribedil in different ionization states were investigated in order to assess its capacity for crossing membranes. The present study showed that piribedil has a relatively high lipophilicity (log P_oct = 2.84) and is a non- or very weak H-bond donor (Δ log P_oct-hep = 0.75), implying optimal properties for transmembranal transport. Based on its microscopic ionization behaviour as studied by ¹³C-NMR spectroscopy and (log P − log P⁺) value (5.04) (a measure of the stability of the ionic vs neutral species in a lipidic phase), protonation proved to be very unfavourable in water-saturated octanol due to the hindrance of solvation by the two bulky groups adjacent to the piperazinyl amino group. In addition, transport of piribedil across a lipophilic membrane was studied according to first-order kinetics in a three-compartment model. The effects of lipophilic counterions on the partitioning behaviour and transfer kinetics were examined and shown to be non-existent at equimolar concentrations.