Species Differences of Drug‐Metabolizing Enzymes

Abstract

The prediction of human pharmacokinetics, efficacy, and toxicity from preclinical data remains an important goal in the drug discovery and development process to minimize risk to participants during first in human studies. Animal models are commonly used in the preclinical development of new drugs; however, significant differences exist between species. These are due largely to alterations in isoform composition, regulation, expression, and catalytic activities of drug‐metabolizing enzymes (DMEs), particularly cytochromes P450 (CYPs), which play a critical role in numerous oxidative reactions of drugs. Although the reliability of animal testing to predict concentration‐dependent efficacy and toxicity in humans has been questioned; it is generally believed that data from animal studies can be reasonably extrapolated to humans using appropriate drug metabolism and pharmacokinetic principles. In this chapter, the authors describe the similarities and differences of major CYPs and other enzymes in their gene and protein structure, catalytic activity, enzyme kinetics and inhibition, and induction response between the various preclinical species and humans. These comparisons help to better understand underlying mechanisms responsible for the differences and address the question of whether animal data can be extrapolated to humans with regard to drug absorption, distribution, metabolism, and excretion. In conclusion, the DMEs show appreciable interspecies differences from structure to function, and caution must be taken when extrapolating metabolism data from animal models to humans.

Developmental Expression of the Cytosolic Sulfotransferases in Human Liver

“…Interspecies variation in the expression of xenobiotic-metabolizing enzymes has been well documented (DeKeyser and Shou, 2012). Marked differences in SULT sequence, expression, and regulation have been reported in multiple studies.…”