Drug discovery data interpretation

From an industrial perspective, quantitative knowledge of the existence of different transporters within the cellular system used in screening procedures is of major importance as it can influence both the predictive value of the permeability coefficients and interpretation of the results. In addition, information on species differences or similarities or discrepancies between cell culture models and animals now provide an important basis for the scaling of data during the early phases of drug discovery for animals or humans [48]. 

Different formulation principles, dosage forms, and DDSs are commonly evaluated in animal models, and attempts are made to predict human absorption on the basis of such studies.80 Human studies are also conducted in some cases to confirm predictions from animal models. Chiou et a 1.81,82 demonstrated that there is a highly significant correlation of absorption (r2 = 0.97) between humans and rats with a slope near unity. In comparison, the correlation of absorption between dog and human was poor (r2 = 0.512) as compared to that between rat and human (r2 = 0.97). Therefore, although dog has been commonly employed as an animal model for studying oral absorption in drug discovery and development, one may need to exercise caution in the interpretation of data obtained. 

The application of chemical inhibitors in studies of this type can provide sound scientific information to make early decisions during drug discovery. However, as the majority of high turnover compounds are screened out, a major proportion of compounds for which phenotyping information is required, are low to intermediate clearance compounds. As such care needs to be taken when interpreting data from more metabolically stable compounds. This is best illustrated for compounds metabolized by more than one CY P, where the inclusion of a specific inhibitor results in no turnover, precluding an exact measurement of a percent contribution. 

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