Evaluation of CYP450 Activities in Diabetic Patients vs. Non-diabetic Subjects
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      Patients with type 2 diabetes (T2D) require various therapeutic approaches (diet, exercise
      and drugs) to ensure glycaemic control while minimizing the risk of hypoglycaemia. T2D is
      also associated with vascular morbidities necessitating multiple drugs to prevent
      cardiovascular complications. Clinical practice reveals that T2D patients show highly
      variable responses to different drugs. Variable drug dosages and effects are observed for
      drugs such as clopidogrel, warfarin, cyclosporine and tacrolimus, as well as for
      anti-hypertensive, cholesterol lowering and antidiabetic drugs. These observations strongly
      suggest that T2D modulates factors regulating drug disposition and/or drug effects.

      The hypothesis underlying this proposal is: T2D and its abnormalities alter the expression
      and activities of CYP450s involved in the disposition of drugs used to treat T2D and
      associated comorbidities.

      The overall objective of this project is to investigate the effects of T2D on the activity of
      several CYP450 isozymes. Primary objective: To compare CYP450 activities between diabetic and
      non-diabetic subjects following a single oral administration of a cocktail of CYP450 probe
      drugs. The secondary objective: To evaluate and compare CYP450 activities according to the
      glycemic control (T2D patients with good glycemic control; T2D patients with poor glycemic
      control; and non-diabetic healthy subjects).

      Study design; Patients (n=126) will be recruited to constitute 3 groups: Group I, 42
      confirmed T2D with HbA1c ≤7.0; Group II, 42 patients with poor glycemic control HbA1c>7.0,
      and Group III, 42 sexed-matched non-T2D healthy subjects. This design will allow us to
      compare CYP450 activities between T2D patients with good glycemic control, T2D patients with
      poor glycemic control, and non-diabetic healthy subjects. Participants will be ≥18 years old,
      with a body weight index ≤35, and be non-smokers (>3 months). Subjects will be recruited at
      the CHUM outpatient clinic. The T2D diagnosis will be established according to the Canadian
      clinical guidelines. After an overnight fast, participants will be admitted to the CRCHUM's
      Clinical Research Unit (they will be not hospitalized). Subjects will receive the CRCHUM-MT
      cocktail; 100mg caffeine, 100mg bupropion, 250mg tolbutamide, 20mg omeprazole, 30mg
      dextromethorphan and 2mg midazolam to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2B6, 2D6 and
      3A4/5, respectively. Serial blood samples will be drawn and urine collected over 8 hours
      following drug administration. At the end of study day, subjects will be discharged from the
      CRCHUM's Clinical Research Unit and an oral 250mg dose of chlorzoxazone (CYP2E1) will be
      given and urine collected overnight for 12 hours.

      A blood sample will be taken for pharmacogenetic analysis for relevant drug metabolizing
      enzymes. Additional blood samples will be collected just before the administration of the
      cocktail to measure insulin, glycaemia and HbA1c levels, biomarkers and inflammatory markers.

      The subjects will be instructed not to take any medication, caffeine or theobromine
      containing products on the morning of study day. Their regular medication will be
      administered 4 hours after the administration of the cocktail if indicated. The subjects in
      whom our probe marker drugs are used daily will still be enrolled as metabolic ratios and
      will be determined to establish CYP450 activities.

      Pharmacokinetic parameters such as oral clearance, metabolic clearance and renal clearance
      will be determined by noncompartmental analysis. Metabolic ratios will be calculated and
      compared between three groups of subjects.
    

Intervention name(s): CRCHUM-MT cocktail
Intervention type(s): Drug
Other intervention name(s): omeprazole; Losec; caffeine; Wake-up; bupropion; Wellbutrin; Zyban; dextromethorphan; midazolam; tolbutamide; chlorzoxazone; Acetazone
Intervention MeSH terms: Tolbutamide; Midazolam; Dextromethorphan; Caffeine; Chlorzoxazone; Bupropion; Omeprazole
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Cytochromes p450; drug metabolism; pharmacokinetics; diabetes; probe markers