Investigations in oral absorption of enalapril maleate.

Abstract

Theory. Drug permeability is one of the most important parameters that influence oral absorption. It is currently being determined by jejunal perfusion with the Loc-I-Gut method. This method was shown to be successful in effective permeability estimation applying the well mixed tank model for this system. In previous studies, human radius R was assumed to have an average of 1.75 cm. In this new approach, the individual segmental dynamic volume is estimated in order to more accurately estimate the individual apparent segmental radius and permeability, and decrease the variability of the estimates. Experimental application. Human and dog permeability of enalapril maleate was utilized as a prototype to validate this new approach. Experiments were performed on 5 healthy human subjects and 4 dogs. This method was then applied theoretically to previous human permeability studies in order to estimate a more accurate human intestinal apparent radius. Results and conclusions. We observed inter-individual variability in apparent small intestinal segment radii. This is suggested to increase the variability in permeability values if a constant radius is used. We also observed intra-individual variability. This is suggested to be due to the segmental volume being a function of intestinal motility and the flow of perfusate out from the segment. It was noticed that individual dynamic volumes are higher at low PEG4000 recovery. This is expected because some of the calculated mass is actually lost due to leakage. In such cases, when PEG4000 recovery is less than 85-90% and shows no steady state pattern, the use of an average value of human apparent intestinal radius of 1.201 cm (1.214 cm for dogs) for effective permeability calculations is suggested. The apparent segmental radius showed a weak correlation with age, height and weight. In addition, inhibition studies in dogs suggested a carrier mediated mechanism of transport for enalapril. Human and dog results were well correlated, suggesting that the dog is a good large animal model for permeability estimation. This new approach will to be used for future human and animal permeability estimations in order to obtain more accurate and less variable estimates.