Modeling Gastrointestinal Drug Absorption Requires More In Vivo Biopharmaceutical Data: Experience from In Vivo Dissolution and Permeability Studies in Humans

Hans      Lennernas

Abstract

The majority (84%) of the 50 most-sold pharmaceutical products in the US and European markets are given orally. The dominating role of this route in drug therapy is a consequence of it being safe, efficient and easily accessible with minimal discomfort to the patient in comparison with other routes of drug administration. A successful drug discovery and development of oral pharmaceutical products require an in-depth understanding of multiple biochemical and physiological processes that determine the dissolution rate, intestinal permeability, gastrointestinal transit, first-pass extraction and systemic exposure-time profiles of drugs. It is crucial to realize that these basic biopharmaceutic and pharmacokinetic properties are crucial to focus on to allow successful drug development. Identification of the rate-limiting step(s) in order to overcome these barriers and understanding of the sources of variability are important in the selection of suitable candidate molecules in drug development. Several reports based on in vitro investigations in various cell models have suggested that carrier-mediated intestinal efflux may be a major reason for incomplete absorption and variable bioavailability of drugs, as well being a site for drug-drug and specific food-drug interactions. However, many drugs which were initially suggested to undergo significant efflux in vitro were later shown to be completely absorbed in vivo. This apparent discrepancy between in vitro and in vivo results may be due to several factors that will be discussed in this review. Novel data on solubility and dissolution in human gastrointestinal derived fluids will be reviewed. The effect of food intake on solubility and dissolution rate of a range of drugs including felodipine, danazol, griseofulvin, cyclosporine, probucol and ubiquinone in simulated and real intestinal fluids is discussed. The biopharmaceutic and physicochemical data discussed here can potentially be used as a benchmark set for validation of new experimental techniques or in silico models in future. Factors such as structural diversity, commercial availability, price and a suitable analytical technique for quantification were considered in the selection of a specific drug set. Using the compiled data set lipophilicity as determined by reverse phase HPLC and permeability across Caco-2 cell monolayers were determined; means to overcome the experimental difficulties due to the diversity of the data are also discussed.

Keywords: bioavailability, QSAR-models, bioequivalence, solubilization, Intestinal permeability

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