Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction.
Animal models are commonly used in the preclinical development of new drugs to predict the metabolic behaviour of new compounds in humans. It is, however, important to realise that humans differ from animals with regards to isoform composition, expression and catalytic activities of drug-metabolising enzymes. In this review the authors describe similarities and differences in this respect among the different species, including man. This may be helpful for drug researchers to choose the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. The authors focus on CYPs, which are the main enzymes involved in numerous oxidative reactions and often play a critical role in the metabolism and pharmacokinetics of xenobiotics. In addition, induction and inhibition of CYPs are compared among species. The authors conclude that CYP2E1 shows no large differences between species, and extrapolation between species appears to hold quite well. In contrast, the species-specific isoforms of CYP1A, -2C, -2D and -3A show appreciable interspecies differences in terms of catalytic activity and some caution should be applied when extrapolating metabolism data from animal models to humans.
Martignoni
Marcella
M
Nerviano Medical Sciences, Preclinical Development, Viale Pasteur 10, Nerviano (MI), Italy. marcella.martignoni@nervianoms.com
Groothuis
Geny M M
GM
de Kanter
Ruben
R
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity
D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System