Species similarities and differences in pharmacokinetics.

Abstract

One of the fundamental challenges drug metabolism scientists face in drug discovery and development is the extrapolation of metabolic data and risk assessment from animals to humans. Although it is generally believed that data from animal studies can be reasonably extrapolated to humans with the application of appropriate pharmacokinetic principles, there are certainly some limitations. The purpose of this review is to show some species similarities and differences in absorption, distribution, metabolism, and excretion, with an attempt to address the questions of whether animal data can be extrapolated and what the limitations are. The underlying mechanisms responsible for these similarities and differences are discussed and examples given for illustration. In addition, the concepts of allometric and physiological models for extrapolation of kinetic data are briefly highlighted. In conclusion, although pharmacokinetics has been advanced greatly in recent years, it is not yet possible to predict all of the pharmacokinetic parameters of a drug in humans from animal studies. Nevertheless, under certain well-defined conditions, it may be possible to make reasonably good predictions. For example, the intrinsic absorption of a given drug across the wall of the gastrointestinal tract is probably similar among species, because the nature of the biomembrane of epithelial cells is similar in mammals and because the absorption process is basically an interaction between the drug and the biomembrane. However, other factors, such as pH-dependent solubility and first-pass metabolism that affect the absorption, may differ from species to species resulting in species differences in absorption. Predicting the renal excretion of drugs in humans has been relatively successful using the glomerular filtration rate ratio between humans and animals. Similarity, if the elimination of a drug is mainly by the liver and the rate of elimination is limited by hepatic blood flow, one could predict the clearance of the drug in humans by the hepatic blood flow. However, biochemical parameters, such as protein binding and drug metabolism, are less predictable. These parameters vary considerably among species.