Phenotypical Approach of the Drug Metabolizing Hormones Activity Before and After Roux-en Y-Gastric Bypass

Study Overview
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Brief Summary
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The activity of drug-metabolizing enzymes and transporters evolutes after Roux-en-Y gastric Bypass. Primary aim : To study the intra individual evolution of phenotypical markers of different drug metabolizing enzymes and one transporter (CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4 and P-gp), using a cocktail phenotypic approach, after Roux-en-Y gastric Bypass.

Detailed Description
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Principal Judgement criteria : Phenotypical markers of enzymes and transporter activity before, at 5-8 weeks and 25-30 weeks following surgery. Secondary judgement criteria : Genetic polymorphisms known to affect expression and/or activity of enzymes and transporter. Intestinal and hepatic expression and activity of the enzymes and transporter of interest. Markers of inflammation Methodology, study design : open-labelled monocentric study. Sample size : It will be a descriptive experimental study involving 12 subjects. Study design : In centre 1: Inclusion at least 2 weeks prior to surgery (V0) In centre 2: Three studies of 12 hours each will occur (in addition with the usual clinical and surgical follow up) at three times periods: in the 8 weeks period before surgery (V1), at 5-8 weeks after surgery (V2) and at 25-30 weeks after surgery (V3). In centre 3: the patients will undergo gastric bypass surgery (corresponding to the usual clinical and surgical follow up) and samples of jejunum and liver will be obtain during the surgery (J0). Centres 4 and 5 are involved in samples analysis.Hence, patients will attend 3 visits, in addition to the usual clinical and surgical follow-up. Study duration: 26 months (with duration of inclusion of 18 months) Duration for a patient: 38 weeks at maximum (8 months) Investigating center and participating units: one center enrolling the patients and three centers involving in the others investigations.

Official Title
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Phenotypical Approach of the Drug Metabolizing Hormones Activity (CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4 and P-gp) Before and After Roux-en Y-Gastric Bypass. The SODA Protocol: Surgery for Obesity and Drug Availability

Conditions
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Obesity

Intervention / Treatment
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* Drug: phenotypical approach


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with morbid obesity (IMC > 40 kg/m²) or severe obesity (IMC=35-40 kg/m²) with co morbidities (sleep apnea syndrome or hypertension without treatment or steatosis hepatitis) candidates for a gastric bypass. Patient not receiving more than two treatments whose effect on the expression of enzymes and drug transporters is zero other than vitamins. Patient agreeing to participate at three studies of one day (12 hours) occurring at three different periods. Patients aged between 18 and 60 years old. Patient giving its well-informed and free consent. Patient without allergy to any of the drugs used for test. Patients living in France during the study and with French social security Exclusion Criteria: Tabacco Contraception including estrogens compounds Medication other than vitamins. Allergy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: phenotypical approach<br>phenotypical approach | Drug: phenotypical approach<br>* each visit : CAFEINE : (solution orale) 2 ampoules de 2 ml = 100 mg de CAFEINE DEXTROMETHORPHANE : 15 ml de sirop contains 20 mg =>22,5 ml = 30mg Midazolam : (solution injectable, ampoule 1 ml = 1 mg) : deux ampoules = 2 mg Digoxine nativelle (solution injectable, ampoule de 0.5mg) : 1 ampoule per os = 0.5 mg Losartan 50 mg : 1cp de 50mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phenotypical markers of enzymes and transporter activity | plasmatic [Paraxanthine/caffeine] ratio (T4H) at 5-8 weeks following surgery. - plasmatic [Omeprazole/5-hydroxyomeprazole] ratio (T4H) at 5-8 weeks following surgery. - urinary Log (dextromethorphan/dextrorphan) (T0-T8h) at 5-8 weeks following surgery. - urinary Losartan/ E-3174 (T0-8h) at 5-8 weeks following surgery. - plasmatic AUC 0-inf midazolam at 5-8 weeks following surgery. - plasmatic AUC 0-inf digoxin at 5-8 weeks following surgery | at 5-8weeks | 
| Phenotypical markers of enzymes and transporter activity | plasmatic [Paraxanthine/caffeine] ratio (T4H) at 25-30 weeks following surgery. - plasmatic [Omeprazole/5-hydroxyomeprazole] ratio (T4H) at 25-30 weeks following surgery. - urinary Log (dextromethorphan/dextrorphan) (T0-T8h) at 25-30 weeks following surgery. - urinary Losartan/ E-3174 (T0-8h) at 25-30 weeks following surgery. - plasmatic AUC 0-inf midazolam at 25-30 weeks following surgery. - plasmatic AUC 0-inf digoxin at 25-30 weeks following surgery | 25-30 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intestinal and hepatic expression and activity of the enzymes and transporter of interest and markers of inflammation | Intestinal and hepatic expression and activity of the enzymes and transporter of interest and markers of inflammation | before surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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drug metabolizing enzymes and drug transporter, Roux-en Y-Gastric Bypass, Obesity, Drug Availability, BMI over 35kg/m² and comorbidities or >40kg/m²