In Vivo Methods

Extrapolation of animal permeability/absorption data to humans should be performed with caution because of potential species differences. Based on the similarity of the composition of epithelial cell membranes of the mammals, and the fact that absorption is basically an interaction between the drug and the biological membrane, permeability across the gastrointestinal tract should be similar across the species. However, there are physiological factors such as pH, GI motility, transit time, and differential distribution of enzymes and transporters that can affect the absorption leading to species variability. Excellent reviews and discussions (Dressman, 1986; Kararli, 1995; Lin, 1995) discuss species similarity and differences in ADME, with an attempt to address the question on limitations in extrapolating data from animals to humans.

Despite the fact that it is extremely resource intensive, in vivo evaluation of drug absorption in laboratory animals is a commonly used method to predict the extent of absorption of drug candidates in humans. Comparison of AUC (plasma concentration vs. time curve) values after intravenous, oral and intraportal (or intraperitoneal) administration can often indicate the absolute extent of in vivo absorption. More common practice for higher throughput in vivo absorption screening is that limited number of blood samples (3-4 time points up to 6 or 8 h) are collected after oral administration. As a result, a larger number of drug candidates can be ranked on the basis of drug concentration in the systemic circulation. It should be recognized that truncated pharmacokinetic studies (with reduced sampling times) are not optimal and the results obtained from such a study may not be accurate. However, the method is capable of differentiating well absorbed compounds from poorly bioavailable compounds.

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