• Development of passive and active absorption models and their relevance to dosage form absorption kinetics

      Lentz, Kimberley Ann; Polli, James E. (2000)
      Permeation models for passive and active mechanisms of intestinal absorption benefit the drug discovery process by predicting in vivo intestinal absorption prior to human clinical trials. Incorporation of these models into a high throughput screening program would also facilitate the identification of lead molecules with good absorption potential early in the drug development process. The objectives of this work were to demonstrate the importance of several in vitro absorption models. The first method involved the development of a more rapid culture system for Caco-2 cells to be used for assessing passive intestinal drug permeation. This model was an improvement over the current 21-day protocol for producing functional, confluent cell monolayers, both in respect to time and materials savings. This system also had application to the FDA's Guidance on Biopharmaceutics Classification System. This model was also applied to studies concerning the role of passive permeability in apparent P-glycoprotein kinetics. Compounds that are substrates for this efflux system exhibit limited intestinal absorption. This work investigated the role that the parallel process of passive transport plays to the extent at which a compound is apparently effluxed. From a more traditional formulation perspective, biopharmaceutic properties were integrated with formulation variables into a model to predict in vivo performance of drug formulations. The findings showed that this system could be used to predict the in vivo performance of a dosage form, prior to clinical testing. Finally, a model to study the Human Intestinal Bile Acid Transporter (hIBAT)-mediated transport of bile acids and prodrugs was developed. Current expression levels of this transporter in the Caco-2 cell line were inconsistent, establishing a need for such a model. Because the human intestinal bile acid transporter has an enormous capacity as a means of drug absorption, this model was used to determine the uptake of an atenolol prodrug, which contained a bile acid moiety. Development of each of these models provided useful tools for the determination of absorption potential for a variety of drugs. Implementation of these methods/results early in the drug discovery process will assist with rational drug development and bringing products to market that have good absorption characteristics.