Clinical trial NCT00981929: Development of Cocktail for Measuring the Activity of Important Cytochrome P450 Enzymes
Official title: Development of Cocktail for Measuring the Activity of Important Cytochrome P450 Enzymes
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Cytochrome P450 Phenotype and Genotype Metrics
Keywords: CYP2D6
CYP2C9
CYP2C19
CYP1A2
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
First posted: 2009-09-22
Enrollment: 412
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: SCREENING

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Healthy volunteers,
* Written consent, AND
* Age 18-65 years old.

Exclusion Criteria:

* Daily medication,
* Alcohol abuse,
* Pregnancy, OR
* Breastfeeding.

Primary outcomes:
measure: Metabolic ratios
timeFrame: January 2011
Secondary outcomes:
measure: Genetic variants
timeFrame: January 2011
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: University of Southern Denmark, Clinical Pharmacology
state: Fyn
Study officials:
References:
citation: Pedersen RS, Damkier P, Christensen MM, Brosen K. A cytochrome P450 phenotyping cocktail causing unexpected adverse reactions in female volunteers. Eur J Clin Pharmacol. 2013 Dec;69(12):1997-9. doi: 10.1007/s00228-013-1561-1. Epub 2013 Aug 6.