|Budget Amount *help
¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 1996 : ¥300,000 (Direct Cost : ¥300,000)
Fiscal Year 1995 : ¥1,700,000 (Direct Cost : ¥1,700,000)
In this study, we investigated the structure-relationship of the transport mechanism of polycationic drugs (di-, tri-and tetraamine compounds) across plasma membrane using rat intestinal brush-border and basolateral membrane vesicles, and rat renal brush-border membrane vesicles.
1. Transport mechanism of polycationic drugs across intestinal brush-border membrane
A good correlation between the initial transport rate of diamine compounds and their lipophilicities. On the other hand, the transport rate of tri-and tetraamine compounds was almost same as diamine compound, although the lipophilicity of tri-and tetraamine were much lower than diamine compounds. A valinomycin induced potassium-diffusion potential (inside-negative) stimulated the initial uptake of diamine compounds by membrane vesicles, and a good correlation was observed between the lipophilicity and the amount of diffusion-potential dependent transport of diamine compounds. However, because of their extremely lower lipophilici
ty, tri-and tetraamine compounds werenot affected by the diffusion potential. Furthermore, membrane surface potential playd a common role in the transport of all polycationic compounds.
2. Transport mechanism of polycationic drugs across intestinal basolateral membrane
There was a specific carrier for putrescine, a diamine compound, in the ratintestinal basolateral membrane. The driving force of this carrier was an inward Na^+ gradient, and transport into the cell. Carrier-mediated transport of putrescine was inhibited by other diamine compounds. Because of that tri- and tetraamine compounds did not affect to the transport, this carrier would recognize only diamine compounds.
3. Transport mechanism of polycationic drugs across renal brush-border membrane
Because of spermine and trientine, tetraamine compounds, trans-stimulated the uptake of spermine by rat renal basolateral membrane vesicles, a specific carrier for tetraamine compounds existed in this membrane. Moreover, in-vitro study, the renal clearance of trientine was faster than creatinine clearance. These data suggest that this transport system contributes to the secretion of tetraamines in the kidney proximal tubule. Less