Effects of LRYGB on Pharmacokinetics of Nine CYP Probe Drugs

Study Overview
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Brief Summary
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Due to anatomical and physiological changes caused by the Roux-en-Y gastric bypass (RYGB) bariatric surgery, drug bioavailability after the surgery can be altered. Therefore, post-operative dose adjustment in these patients can be required. The aim of the study was to investigate the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery on drug pharmacokinetics and cytochrome P450 (CYP) mediated metabolism using a cocktail of nine CYP probe drugs. The cocktail covers nine main CYP enzymes: melatonin (CYP1A2), nicotine (CYP2A6), bupropion (CYP2B6), repaglinide (CYP2C8), losartan (CYP2C9), omeprazole (CYP2C19/CYP3A4), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1), midazolam (CYP3A4). The changes in pharmacokinetic parameters of the drugs as well as modulation of the activity of CYPs are evaluated before and one year after LRYGB. In the study, the patients administering drug cocktail before surgery and 1 year after LRYGB are served as their own controls.

Official Title
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Altered Metabolism of Nutrients and Drugs in Obesity and After Obesity Surgery

Conditions
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Obesity, Morbid, Bariatric Surgery Candidate

Intervention / Treatment
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* Drug: cocktail of nine CYP probe drugs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI > 40 kg/m2 or BMI 35-40 kg/m2 and a comorbidity or its risk factor, such as type 2 diabetes, hypertension, sleep apnea, osteoarthritis of weight bearing joints or polycystic ovarian syndrome; previous conservative treatment for obesity had been proven to be ineffective; patients were assigned to undergo LRYGB surgery patients are able to give a written inform consent. Exclusion Criteria: smokers consuming alcohol more than 20 g per day were included in the study taking drugs which alter CYPs activity history of hypersensitivity to the drugs used in the cocktail

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: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phenotyping cocktail of 9 CYP probe drugs before surgery<br> | Drug: cocktail of nine CYP probe drugs<br>* Two equally loaded capsules containing: Melatonin (2.0 mg) Nicotine (1.0 mg) Bupropion (37.5 mg) Repaglinide (0.25 mg) Losartan (12.5 mg) Omeprazole (10 mg) Chlorzoxazone (62.5 mg) Midazolam (1.85 mg) Dextromethorphan (30 mg) as an oral solution was administered separately after the capsules.<br>|
| Experimental: Phenotyping cocktail of 9 CYP probe drugs 1 year after surgery<br> | Drug: cocktail of nine CYP probe drugs<br>* Two equally loaded capsules containing: Melatonin (2.0 mg) Nicotine (1.0 mg) Bupropion (37.5 mg) Repaglinide (0.25 mg) Losartan (12.5 mg) Omeprazole (10 mg) Chlorzoxazone (62.5 mg) Midazolam (1.85 mg) Dextromethorphan (30 mg) as an oral solution was administered separately after the capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probe cocktail drugs concentration-time profile in plasma and urine before LRYGB |  | baseline, 1 hour, 2 hour, 4 hour and 6 hour | 
| Probe cocktail drugs concentration-time profile in plasma and urine 1 year after LRYGB |  | baseline, 1 hour, 2 hour, 4 hour and 6 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic ratios of parent compounds and corresponding metabolites before LRYGB |  | baseline, 1 hour, 2 hour, 4 hour and 6 hour | 
| Metabolic ratios of parent compounds and corresponding metabolites 1 year after LRYGB |  | baseline, 1 hour, 2 hour, 4 hour and 6 hour |