The Intestinal Permeability Studies of Three Non-Peptidic HIV Protease Inhibitors
Youn, Anthony S.
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The nonpeptidic HIV protease inhibitors represent a novel approach of combating the virus associated with AIDS. While peptidic HIV protease inhibitors have been characterized by low intestinal bioavailability due to transport by paracellular diffusion, the nonpeptidic HIV protease inhibitors are believed to be transported by passive diffusion, a more efficient means of intestinal absorption. When three nonpeptidic HIV protease inhibitors were recently tested in rats, they exhibited very different bioavailabilities. Some of these differences might be caused by variations in intestinal permeability and solubility. Therefore, an in situ rat mesenteric vein absorption model was employed to measure intestinal permeability coefficients. Validation of the model consisted of determining the adsorptive effects of various infusion pump tubings, a suitable method for accurate gut measurements, and the effects of drug formulation and concentration on intestinal permeability. Analysis of permeability coefficients determined from the appearance of drug in the mesenteric blood and solubilities for the three inhibitors suggest that both permeability and solubility may have a significant effect on bioavailability. Permeability coefficients determined from the disappearance of drug from the intestine were indistinguishable from appearance permeability for U-96988. Disappearance permeability was significantly larger than 1 appearance permeability for U-103299, suggesting that this compound might have been metabolized during transport. While this study has provided information on possible factors affecting bioavailability, further investigation is required to delineate quantitative contributions of each factor.