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 de termined using an in vitro model involving everted intestinal sacs of rat. Degradation of leuprolide by intestinal proteolytic enzymes was s uppressed with a mixture of protease inhibitors which was shown to com pletely inhibit degradation in separate experiments using intestinal h omogenates. This allowed the true permeability coefficient of leuproli de to be determined. The enhancement of this intestinal permeability b y the Igepal CO(R) homologue series of surfactants was investigated us ing members of this series with hydrophilic-lipophilic balance values (HLB) ranging between 12 and 19. Enhancement showed a non-monotonic de pendence on HLB with a maximum at HLB approximate to 15, while at both lower and higher HLB values an enhancement decrease was observed. Sur factant uptake into the tissue showed a similar non-monotonic dependen ce on HLB. On the other hand, red blood cell lysis and lecithin solubi lization potencies of the Igepal CO showed a monotonic decrease with i ncreasing HLB within the HLB range studied. Hence, it is suggested tha t the process of permeation enhancement should be dissociated from tha t of membrane solubilization in terms of the mechanism of surfactant-m embrane interaction. While membrane disruption, for example, in the ca se of hemolysis, seems to be correlated with phospholipid solubilizati on it does not appear to be a prerequisite for permeation enhancement. Permeability increase of the plasma membrane may conceivably be accom plished by surfactant incorporation into the bilayer causing highly pe rmeable disorder points and/or an increased membrane fluidity.