Variabilité interindividuelle dans la réponse aux médicaments : rôle des déterminants extra-hépatiques, influence de conditions physiopathologiques et de la pharmacogénétique dans le métabolisme des médicaments

 

Véronique Michaud

Centre hospitalier de l'Université de Montréal

 

Domaine : nutrition et métabolisme

Programme chercheurs-boursiers - Junior 1

Concours 2014-2015

Drug-related morbidity is an important public health concern affecting both clinical outcomes and healthcare costs. In Canada, it is estimated that more than 10,000 people die every year (4th leading cause of death in USA) because of inappropriate drug use or drug effects. Some drugs exhibit limited efficacy in some patient subpopulations but worse, certain drugs can cause severe toxicities. Among patient subpopulations of interest is surely the 285 million patients presenting with type-2 diabetes (T2D). Patients with T2D represent a particular interest in practice because of the number of drugs required to treat the hyperglycaemia status and prevent cardiovascular comorbidities. These cardiovascular complications remain difficult to prevent since some T2D patients appear resistant to certain drugs. To the contrary, others are more sensitive to some other drugs. As such, the management of concomitant drug therapies is difficult and requires the use of highly variable drug doses. On average, patients with T2D may take up to 8-10 drugs per day. Consequently, significant drug-drug interactions and large interindividual variability are observed among T2D patients. I propose to evaluate the contribution of the major system involved in drug elimination (CYP450 drug-metabolizing enzymes) with special attention to the role of disease state, focusing on T2D. Another important factor taken into consideration throughout my project is the determination of drug concentrations not only in plasma but more specifically in tissues, i.e., at the vicinity of drug action sites.

The aim of this project is to study in depth factors pertaining to intersubject variability in drug action in specific patient subpopulations: 1) the influence of T2D and its co-morbidities on drug metabolism, 2) drug metabolism in extra-hepatic tissues and 3) pharmacogenomics. The acquired knowledge will contribute to reducing drug inefficacy and toxicities by better adjusting drug dose or selecting more appropriate drugs.