Study investigating metabolomics (analysis of molecules produced from cell activity) as a new measurement method for liver enzyme function

INTERVENTION: Participants are recruited based on their CYP2C9 genotype. This is blinded to the participant and the research team by a third party. The study is a crossover design, so participants will be treated with placebo or Fluconazole before each study day. The order of placebo and fluconazol is blinded to the participant and the researcher. The medication is packed and randomized by the Pharmacy (third party). This is a recruitment‐by‐genotype randomised and placebo controlled double‐blind cross‐over study design. For those recruited from Generation Scotland (GS), GoDARTS and GoSHARE, study visits will take place in the Clinical Research Centre (CRC), Ninewells Hospital & Medical School, Dundee. Each volunteer will be on study for two weeks in total. This includes two distinct treatment periods of each 2 days duration, separated by at least one week wash‐out period (Debruyne and Ryckelynck 1993). Participants will receive their participant information sheet a few days prior to the screening visit. At the baseline / screening visit, participants will have vital signs, height, weight, and BMI measured. Blood and urine samples will be obtained. Medical history including current prescriptions, history of smoking and alcohol use. The outline and purpose of the experiment will be explained, and information will also be supplied in writing, and consent will be obtained. Participants will be supplied with one fluconazole capsule for study day 1, at the end of the screening visit. If a participant is excluded from the study, then the drugs will be returned to the relevant CRC. Participants will undertake 2 study days. On study day 1 (tolbutamide w/o fluconazole), a baseline blood sample for metabolomics w CONDITION: Impact of CYP2C9 genotype and CYP2C9 inhibiting drugs in healthy volunteers ; Not Applicable PRIMARY OUTCOME: ; 1. Level of tolbutamide, and in the blood measured with UHPLC‐MS/MS using blood samples taken at 0, 0.5, 1, 2, 3, 4, 6 hrs, derive pharmacokinetic parameters from measures (CL, T1/2, AUC); 2. Level of tolbutamide, 4‐hydroxytolbutamide and carboxytolbutamide in the urine measured with UHPLC‐MS/MS using urine samples collected from 0 to 12 hours and from 12 to 24 hours; 3. Metabolomics (Metabolon, MS/MS) will measured on T=0 hr samples; SECONDARY OUTCOME: There are no secondary outcome measures INCLUSION CRITERIA: 1. Aged 18 ‐ 60 years 2. Caucasian (to limit genetic variation as much as possible) 3. Not known to have diabetes 4. No daily treatment with antidiabetic medication, statins, amitriptyline or other drugs that inhibit or require CYP2C9 or CYP3A4 metabolism 5. No cognitive impairment or visual impairment 6. Known CYP2C9 genotype – either normal (“wild type”) or two reduced function alleles