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

2014-08-27 03:19:10 | BioPortfolio


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.

Study Design

Allocation: Non-Randomized, Control: Active Control, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Screening


Cytochrome P450 Phenotype and Genotype Metrics


Tramadol, Omeprazole, losartan, caffeine, Tramadol, omeprazole, losartan, caffeine


University of Southern Denmark, Clinical Pharmacology




University of Southern Denmark

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:19:10-0400

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Medical and Biotech [MESH] Definitions

A cytochrome P-450 monooxygenase that can be induced by polycyclic aromatic xenobiotics in the liver of human and several animal species. This enzyme is of significant clinical interest due to the large number of drug interactions associated with its induction and its metabolism of THEOPHYLLINE. Caffeine is considered to be a model substrate for this enzyme. CYP1A2 activity can also be increased by environmental factors such as cigarette smoking, charbroiled meat, cruciferous vegetables, and a number of drugs including phenytoin, phenobarbital, and omeprazole.

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