Development of Cocktail for Measuring the Activity of Important Cytochrome P450 Enzymes

Study Overview
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Brief Summary
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The Cytochrome P450 enzymes are responsible for the metabolism of a wide range of drugs and other xenobiotics. Genetic variants of the encoding P450 genes have shown to influence the rate of metabolism of many clinically used drugs. The drugs tramadol, omeprazole, losartan, quinidine and caffeine reflect the activity of CYP2D6 (tramadol), CYP2C19 (omeprazole), CYP2C9 (losartan), CYP1A2 (caffeine) and CYP3A4/5 (quinidine). The aim of the study is to investigate if the cocktail of tramadol, omeprazole, losartan and caffeine can be used to simultaneously determine the activity of CYP2D6, CYP2C19, CYP2C9 and CYP1A2. Furthermore, will the natural occurring 4-beta-hydroxy-cholesterol in the blood be measured as a metric for CYP3A4/5. The study is divided in two. First part will include 12 healthy volunteers and consists of three arms separated by at least one week. In the first arm 50 mg of tramadol will be ingested and urine will be collected for 8 hours. In the second arm 20 mg omeprazole, 25 mg losartan and 200 mg caffeine will be ingested followed by 8 hours urine collection and a blood sample 4 hours after administration of the drugs. In the last arm 50 mg of tramadol, 20 mg omeprazole, 25 mg losartan and 200 mg caffeine will be ingested followed by 8 hours urine collection and a blood sample 4 hours after administration of the drugs. Metabolic ratios will be calculated based on urine and plasma concentrations of the drugs and the relevant metabolites. Relevant genetic variants of the cytochrome P450 encoding genes will be determined. If the metabolic ratios of the drugs are not significantly different between the arms, Second part of the study will be conducted. This part is identical with the last arm and will include a maximum of 400 healthy volunteers: 50 mg of tramadol, 20 mg omeprazole, 25 mg losartan and 200 mg caffeine will be ingested followed by 8 hours urine collection and a blood sample 4 hours after administration of the drugs.

Official Title
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Development of Cocktail for Measuring the Activity of Important Cytochrome P450 Enzymes

Conditions
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Cytochrome P450 Phenotype and Genotype Metrics

Intervention / Treatment
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* Drug: Tramadol
* Drug: Omeprazole, losartan, caffeine
* Drug: Tramadol, omeprazole, losartan, caffeine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers, Written consent, AND Age 18-65 years old. Exclusion Criteria: Daily medication, Alcohol abuse, Pregnancy, OR Breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tramadol<br>CYP2D6 metric | Drug: Tramadol<br>* 50 mg single oral dose<br>|
| Active Comparator: Omeprazole, losartan, caffeine<br>CYP2C19, CYP2C9 and CYP1A2 metrics | Drug: Omeprazole, losartan, caffeine<br>* 20 mg omeprazole 25 mg losartan 200 mg caffeine<br>|
| Active Comparator: Tramadol, omeprazole, losartan and caffeine<br>CYP2D6, CYP2C19, CYP2C9 and CYP1A2 metrics | Drug: Tramadol, omeprazole, losartan, caffeine<br>* 50 mg tramadol 20 mg omeprazole 25 mg losartan 200 mg caffeine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic ratios |  | January 2011 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genetic variants |  | January 2011 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CYP2D6, CYP2C9, CYP2C19, CYP1A2