Cocktail Approach for Cytochrome P450 and P-glycoprotein Activity Assessment Using Dried Blood Spot
Study Details
Study Description
Brief Summary
Phenotyping is an approach largely used for the evaluation of the activity of cytochromes and transporters in vivo. It consists of the administration of probe substances metabolised by a specific cytochrome or transported by P-glycoprotein (P-gp) for example, followed by the determination of a metabolic ratio or the evaluation of the plasmatic or urinary concentrations of the probe substances. The administration of a cocktail containing several probe substances allows the simultaneous evaluation of the activity of several cytochromes and P-gp in a single test.
The aim of this project is the validation of a phenotyping cocktail of low dose probe drugs for the assessment of cytochrome P450 and P-gp activities by simple capillary blood sampling and dried blood spot (DBS) analysis. The cocktail consists of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam and fexofenadine for the simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CAP2C19, CYP2D6, CYP3A4 and P-gp, respectively.
The modulation of the activity of cytochromes or P-gp will be evaluated by the administration of inhibitors (fluvoxamine, voriconazole, quinidine) or inducer (rifampicin) of the metabolic pathways or the P-gp mediated transport.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Active Comparator: CYP1A2, 2B6, 2C9, 2C19, 3A4 inhibitors Oral intake of fluvoxamine (50 mg per day during 2 days) and voriconazole (400 mg) before oral intake of the cocktail probe drugs |
Drug: Cocktail probe drugs
Other Names:
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Active Comparator: CYP2D6 and P-gp inhibitor Oral intake of quinidine (200 mg) before oral intake of the cocktail probe drugs |
Drug: Cocktail probe drugs
Other Names:
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Active Comparator: CYPs and P-gp inducer Oral intake of rifampicin (600 mg per day during 7 days) before oral intake of the cocktail probe drugs |
Drug: Cocktail probe drugs
Other Names:
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Experimental: Probe cocktail alone Oral intake of the cocktail probe drugs : bupropion 25 mg flurbiprofen 25 mg omeprazole 5 mg dextromethorphan 5 mg midazolam 1 mg fexofenadine 25mg Caffeine (a cup of coffee) |
Drug: Cocktail probe drugs
Other Names:
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Outcome Measures
Primary Outcome Measures
- Probe cocktail drugs plasma and capillary concentrations in presence/absence of CYP1A2,2B6, 2C9, 2C19, 2D6, 3A4 and P-gp inhibitor or inducer [4 singles days spaced out with one week wash-out periods]
Secondary Outcome Measures
- correlation between plasma or urine and capillary concentrations for each probe cocktail drug [4 singles days spaced out with one week wash-out periods]
- comparison. between genotype and phenotype for each enzyme [one day]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Healthy male volunteers aged from 18 to 60 years
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BMI between 18 and 25
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Understanding of French language and able to give a written inform consent.
Exclusion Criteria:
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Smoker
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Taking drugs which alter CYPs activity
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Renal or hepatic impairment
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Medical history of porphyria
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Medical history of chronic alcoholism or abuse of psychoactive drugs
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Liver transplantation
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Sensitivity to any of the drugs used
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Wearing contact lenses (risk of coloration with rifampicin)
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ECG showing long QT interval (>0.46sec)
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Alteration of hepatic tests
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Presenting genetic polymorphism of poor CYP 2B6, 2C9, 2C19, 2D6 metabolisers
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | University Hospitals | Geneva 14 | Switzerland |
Sponsors and Collaborators
- Jules Desmeules
Investigators
- Principal Investigator: Jules A Desmeules, Pr, University Hospital, Geneva
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Coktail DBS