| Description |
There has been a continuing need for a better quantitative understanding of the gastrointestinal absorption of highly lipophilic drugs. With this aim in mind, the present study describes a physical model approach applicable to understanding the transport of lipophilic, ionizable drugs across a lipophilic membrane. In Chapter 3, model predictions were compared to experimental results of capric acid (HA) transport across a silicone polymer membrane in the presence and in the absence of 2-hydroxypropyl-β-cyclodextrin (HPB). Model predictions and experimental results were generally in agreement over the entire studied ranges of pH and HPB concentrations. In Chapter 4, the physical model approach was then applied to the in situ single pass perfusion system involving the rat ileum to obtain a more detailed understanding about cyclodextrin as an intestinal drug absorption enhancer through its role as a carrier. Model predictions were found to be generally in good agreement with experimental results. We also extended this model to account for the villus structure of the small intestine, resulting in equally good agreement. Both models demonstrated that HPB was able to reduce the capric acid concentration gradient across the aqueous boundary layer and increase the effective intestinal membrane surface area utilized for permeant absorption due to deeper penetration of the permeant into the villus crypts, accounting for the HPB-enhanced permeant flux. In an exploratory investigation (Chapter 5), the in situ single pass perfusion technique was then used to examine the ability of two well known chemical permeation enhancers of hydrophilic drug molecules, sodium caprate (HA) and sodium chenodeoxycholate (CDC), to enhance mannitol transport in the rat ileum in the presence and absence of different cyclodextrin carriers. Analysis of the experimental results with the villus model (VM) support the interpretation that an appropriate enhancer/carrier combination may (1) be able to increase the fraction of ileum surface area that is enhanced and, because of this, that (2) local toxicity effects of the enhancer might be avoided or reduced for any given mannitol permeability enhancement, while (3) at the same time provide increased enhancer duration of action. |
