INTESTINAL PERMEATION AND METABOLISM OF A MODEL PEPTIDE (LEUPROLIDE) AND MECHANISMS OF PERMEATION ENHANCEMENT BY NONIONIC SURFACTANTS

The intestinal permeability of leuprolide, a model nonapeptide; was determined using an in vitro model involving everted intestinal sacs of rat. Degradation of leuprolide by intestinal proteolytic enzymes was suppressed with a mixture of protease inhibitors which was shown to completely inhibit degradation in separate experiments using intestinal homogenates. This allowed the true permeability coefficient of leuprolide to be determined. The enhancement of this intestinal permeability by the Igepal CO(R) homologue series of surfactants was investigated using members of this series with hydrophilic-lipophilic balance values (HLB) ranging between 12 and 19. Enhancement showed a non-monotonic dependence on HLB with a maximum at HLB approximate to 15, while at both lower and higher HLB values an enhancement decrease was observed. Surfactant uptake into the tissue showed a similar non-monotonic dependence on HLB. On the other hand, red blood cell lysis and lecithin solubilization potencies of the Igepal CO showed a monotonic decrease with increasing HLB within the HLB range studied. Hence, it is suggested that the process of permeation enhancement should be dissociated from that of membrane solubilization in terms of the mechanism of surfactant-membrane interaction. While membrane disruption, for example, in the case of hemolysis, seems to be correlated with phospholipid solubilization it does not appear to be a prerequisite for permeation enhancement. Permeability increase of the plasma membrane may conceivably be accomplished by surfactant incorporation into the bilayer causing highly permeable disorder points and/or an increased membrane fluidity.