Visualizing drug efficacy in vivo.
Many enzymes are therapeutic targets for drug discovery, whereas other enzymes are important for understanding drug metabolism and pharmacokinetics during compound testing in animals. Testing of drug efficacy and metabolism in an animal model requires the measurement of disease endpoints as well as assays of enzyme activity in specific tissues at selected time points during treatment. This requires the removal of tissue and biochemical assays. Techniques to noninvasively assess drug effects on enzyme activity using imaging technology would facilitate understanding of drug efficacy, pharmacokinetics, and drug metabolism. Using a commercially available cytochrome P-450 3A substrate whose oxidized product is a luciferase substrate, we show for the first time that cytochrome P-450 enzyme activity can be measured in vivo in real time by bioluminescent imaging. This imaging approach could be applicable to study drug effects on therapeutic target enzymes, as well as drug metabolism enzymes.
Weisheng
Zhang
Z
Xenogen Corporation, Alameda, CA 94501, USA. wzhang@xenogen.com
Min
Chen
C
West
David B
DB
Purchio
Anthony F
AF
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000493:pharmacokinetics*; D003952:Diagnostic Imaging; D004790:Enzyme Induction; D017930:Genes, Reporter; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D008565:Membrane Proteins
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D003907:Dexamethasone; D004364:Pharmaceutical Preparations; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins