Grant: Operating Grant

Conventional concepts in pharmacokinetics propose that enzymes (CYP450s) in the liver and intestines are key determinants of the systemic exposure to a drug. As well, it is known that the free drug concentration in tissues is an important factor to consider while predicting drug action and toxicity. In that sense, our laboratories have accumulated data indicating the expression of drug metabolizing enzymes in the heart (human and animal species) and suggesting their role in the control of intracardiac concentrations of drugs. Therefore, we propose to conduct the first study characterizing the functional activities of CYP450s in human heart tissues. Indeed, we were the first laboratory in the world to develop a reliable method for the preparation of human cardiac microsomes that retain metabolic activities. We also have a unique access to 180 human ventricular samples from explanted hearts of patients who underwent cardiac transplant and 7 normal hearts that could not be transplanted. Using these tissues, we have demonstrated the presence of CYP450 mRNAs in the largest cohort of human ventricular samples ever studied. Our next steps are to demonstrate the functional activity of these enzymes, to characterize the specific activity of various isoenzymes using probe drug substrates, to determine the functional activities of theses isozymes towards the metabolism of selected cardiovascular drugs, and finally, to demonstrate that local metabolism of these drugs can effectively change their action. Our study will provide us with very valuable information helping us better understand inter-subject variability in drug action and toxicity. This will also establish the basis for the development of better drug regimen for the treatment of cardiovascular diseases.