Identification of New Tools for Predicting Natural Metabolic Performance of the Liver

CYP2C19 is involved in the metabolism of approximately 6.8% of all marketed drugs. Its enzymatic activity varies significantly between individuals due to genetic polymorphisms, environmental factors, ethnicity, or disease states. While the administration of a CYP2C19 probe drug, such as omeprazole, is a reliable method for phenotyping this enzyme, it is relatively invasive and not suitable for certain vulnerable populations, such as pregnant women.

Identifying an endogenous compound metabolized by CYP2C19 could provide a non-invasive alternative to conventional phenotyping methods. This clinical study aims to identify such endogenous biomarkers by evaluating the effects of genetic variation, enzyme inhibition and induction on the metabolome of healthy volunteers.

To achieve this, untargeted metabolomic profiling using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) will be conducted on plasma, extracellular vesicles and urine samples.

This single-centre, open-label clinical trial will enroll 40 healthy participants (both men and women), aged 18 to 65 years. Participants will be assigned to one of two groups based on their CYP2C19 genotype: poor metabolizers (PMs) and normal, rapid, or ultrarapid metabolizers (NMs, RMs, UMs).

Each participant will undergo three study sessions:

Session 1: CYP2C19 phenotyping following a single 10 mg oral dose of omeprazole.

Session 2: Identical to Session 1, but following a 7-day pretreatment with fluvoxamine (CYP2C19 inhibitor, 50 mg once daily).

Session 3: Identical to Session 1, but following a 10-day pretreatment with rifampicin (CYP2C19 inducer, 600 mg once daily).

In all sessions, urine will be collected for 24 hours and venous blood samples will be taken prior to omeprazole administration for metabolomics analysis. Capillary blood will also be sampled after omeprazole intake to assess the CYP2C19 phenotype.

Inclusion criteria

• Healthy men and women
• Age 18-65 years
• Body Mass Index (BMI) 18-27
• Understanding of French language and able to give a written inform consent
• CYP2C19 genotype: PMs, NMs, RMs or UMs
• At least one barrier method contraception during the whole study and 1 month after the end of the study (in addition of hormonal contraception if applicable)

Exclusion criteria

• CYP2C19 IMs
• Participation in any other interventional clinical study within 3 months prior to inclusion
• Pregnant or breastfeeding woman
• Any pathologies, use of drugs or food that may affect CYP activity (based on the 'drug interactions and cytochromes P450 table published by the Service of Clinical Pharmacology and Toxicology, HUG50 and on the investigator's knowledge)
• Medical history of liver transplantation
• Regular smokers of ≥ 10 cigarettes/day
• Alcohol intake 2 days prior to session 1 and during fluvoxamine and rifampicin intake
• Alteration of hepatic tests (ASAT, ALAT, GGT, bilirubin more than 3x normal)
• Renal failure (serum urea, serum creatinine and eGFR outside the norms)
• Medical history of chronic alcoholism or abuse of psychoactive drugs
• Sensitivity to any of the drugs used
• Psychiatric disorders
• Beck Score ≥10 (question related to suicide >0)
• Contact lens wearers