Evaluation of CYP450 Activities in Diabetic Patients vs. Non-diabetic Subjects
Status:
Completed
Trial end date:
2019-07-01
Target enrollment:
Participant gender:
Summary
Type 2 diabetes (T2D) could modulate CYP450 activities involved in drug-metabolism and
cardiovascular homeostasis. We propose to carry out, for the first time, a comprehensive
characterization of the effects of T2D on the expression and activity of major CYP450s. In
our studies, patients with T2D will be studied since hyperglycaemia and/or hyperinsulinemia
are believed to modulate CYP450s. This vicious cycle puts patients at risk of micro- and
macro-vascular complications and inadequately controlled T2D due to high intersubject
variability in drug disposition and action.
Characterization of the effects of T2D on drug metabolism capacity will be performed using a
cocktail of CYP450 probe drugs.
CYP450 phenotype will be determined in 3 groups of patients (n=126 patients): 1) 42 T2D
patients with good glycemic control; 2) 42 T2D patients with poor glycemic control; and 3) 42
non-T2D healthy subjects following a single oral administration of a cocktail of CYP450 probe
drugs. Subjects will receive the CRCHUM-MT cocktail consisting of caffeine (CYP1A2),
bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6),
midazolam (CYP3A4/5) and chlorxozaxone (which will be administered separately) (CYP2E1).
Serial blood samples will be drawn and urine collected. Metabolic ratios will be calculated
and compared between three groups of subjects. Other co-variables to be studied include T2D
biomarkers at baseline (glucose, insulin, HbA1c), medications, genetic polymorphisms and
inflammatory markers.
Our cocktail probe drug approach should allow us to demonstrate the effects of T2D on the
activity of major CYP450s. Moreover, this project will indicate to us whether glycemic
control should be considered as a covariate of intersubject variability in drug metabolism
capacity.