Evaluation of CYP450 Activities in Diabetic Patients vs. Non-diabetic Subjects

• Status: Completed
• Trial end date: 2019-07-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
• Collaborator: Canadian Institutes of Health Research (CIHR)
• Treatments: Bupropion; Caffeine; Chlorzoxazone; Dextromethorphan; Midazolam; Omeprazole; Tolbutamide

Criteria

Inclusion Criteria:

• Participants will be ≥18 years old

• Body weight index ≤35,

• Non-smokers (>3 months)

• Patients with type 2 diabetes and good glycemic control (A1C<7) or poor glycemic control (A1C>7.0) and healthy non-diabetic subjects will be eligible.

Exclusion Criteria:

• Subjects with estimated glomerular filtration (MDRD) <50mL/min/1.73m2

• ALT and AST 3 times above the upper limit of normal

• Organ transplant recipient, inflammatory illnesses (i.e., polyarthritis, severe cirrhosis, infectious diseases, heart failure, HIV, hepatitis)

• Previous history of or an active cancer (except non-melanoma skin cancer)

• Uncontrolled thyroid functions

• Pregnant

• History of drug or alcohol abuse

• Subjects with a history of or current inflammatory bowel diseases including ulcerous colitis and Crohn's disease, and bariatric surgery

• Drugs known to modulate CYP450 activities, subject taking one of the following therapies will be excluded: antibiotics, antivirals, anticancers, CYP450 inducers (carbamazepine, phenobarbital, phenytoin, rifampin, St-John's wort), CYP450 inhibitors (amiodarone, fluvoxamine, fluoxetine, verapamil), immunosuppressors, warfarin, INFs, antibodies or grapefruit juice (<2-4 weeks) , CYP450 drugs with strong affinity for the selected isoform and with a long half-life, CYP450 mechanism-based inhibitors or an investigational drug

• Intolerance or hypersensitivity to probe drugs in the CRCHUM-MT cocktail or chlorzoxazone/acetaminophen