Abstract
Animal models are routinely used in drug and chemical safety assessment and in defining the pharmacokinetic/pharmacodynamic properties of drug candidates. The application of models humanised for xenobiotic metabolising enzymes can markedly improve the accuracy of data extrapolation to man. Cytochrome P450s, CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. In order to establish the relative contribution of these enzymes in drug metabolism in vivo we have used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. Using the differential sensitivity of the human enzymes to the inhibitor quinidine we have developed an enzyme kinetic approach to distinguish the relative role of CYP1A1 or CYP1A2 in drug metabolism.
SIGNIFICANCE STATEMENT Human CYP1A1 and CYP1A2 are important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. In the light of differences in substrate specificity and sensitivity to inhibitors, it is of central importance to understand their relative role in foreign compound metabolism. To address this issue, we have generated mice humanized or nulled at the Cyp1a gene locus and through the use of these mouse lines and selective inhibitors, developed an enzyme kinetic-based model to enable more accurate prediction of the fate of new chemicals in man, and which can be validated in vivo using mice humanised for cytochrome P450-mediated metabolism.
- cytochrome P450
- enzyme inhibitors
- enzyme kinetics
- genetically modified animal models
- pharmacokinetic/pharmacodynamic modeling/PKPD
- pharmacokinetics
- physiologically-based pharmacokinetic modeling/PBPK
- The American Society for Pharmacology and Experimental Therapeutics
