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The Basel Cocktail for Simultaneous Phenotyping of Human Cytochrome P450 Isoforms in Plasma, Saliva and Dried Blood Spots

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Abstract

Background and Objective

Phenotyping cocktails use a combination of cytochrome P450 (CYP)-specific probe drugs to simultaneously assess the activity of different CYP isoforms. To improve the clinical applicability of CYP phenotyping, the main objectives of this study were to develop a new cocktail based on probe drugs that are widely used in clinical practice and to test whether alternative sampling methods such as collection of dried blood spots (DBS) or saliva could be used to simplify the sampling process.

Methods

In a randomized crossover study, a new combination of commercially available probe drugs (the Basel cocktail) was tested for simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Sixteen subjects received low doses of caffeine, efavirenz, losartan, omeprazole, metoprolol and midazolam in different combinations. All subjects were genotyped, and full pharmacokinetic profiles of the probe drugs and their main metabolites were determined in plasma, dried blood spots and saliva samples.

Results

The Basel cocktail was well tolerated, and bioequivalence tests showed no evidence of mutual interactions between the probe drugs. In plasma, single timepoint metabolic ratios at 2 h (for CYP2C19 and CYP3A4) or at 8 h (for the other isoforms) after dosing showed high correlations with corresponding area under the concentration–time curve (AUC) ratios (AUC0–24h parent/AUC0–24h metabolite) and are proposed as simple phenotyping metrics. Metabolic ratios in dried blood spots (for CYP1A2 and CYP2C19) or in saliva samples (for CYP1A2) were comparable to plasma ratios and offer the option of minimally invasive or non-invasive phenotyping of these isoforms.

Conclusions

This new combination of phenotyping probe drugs can be used without mutual interactions. The proposed sampling timepoints have the potential to facilitate clinical application of phenotyping but require further validation in conditions of altered CYP activity. The use of DBS or saliva samples seems feasible for phenotyping of the selected CYP isoforms.

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Acknowledgments

The authors thank Claudia Blasi and Luisa Baselgia for their assistance with the clinical study, and Beatrice Vetter for technical assistance.

Author Contributions

Massimiliano Donzelli, contributed to the study design, data analysis and drafting of the manuscript. Adrian Derungs contributed to the study design, conduct of the study and data analysis. Lana Nezic contributed to the conduct of the study. Maria-Giovanna Serratore contributed to the analytical tools and data analysis. Christoph Noppen contributed to the analytical tools and data analysis. Stephan Krähenbühl contributed to the study design and data analysis. Manuel Haschke contributed to the study design, data analysis and drafting of the manuscript.

Disclosures

This study was financed by the Division of Clinical Pharmacology & Toxicology, University Hospital Basel (Basel, Switzerland).

Conflicts of Interest

The authors have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel, Basel, Switzerland

    Massimiliano Donzelli, Lana Nezic, Stephan Krähenbühl & Manuel Haschke

  2. Viollier AG, Allschwil, Switzerland

    Maria-Giovanna Serratore & Christoph Noppen

  3. Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, Hebelstrasse 2, 4031, Basel, Switzerland

    Manuel Haschke

  4. Division of Clinical Pharmacology and Toxicology, Inselspital Bern, Bern, Switzerland

    Adrian Derungs

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  1. Massimiliano Donzelli
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  2. Adrian Derungs
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  7. Manuel Haschke
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Corresponding author

Correspondence to Manuel Haschke.

Additional information

M. Donzelli and A. Derungs contributed equally to this work.

ClinicalTrials.gov ID: NCT01187862.

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Donzelli, M., Derungs, A., Serratore, MG. et al. The Basel Cocktail for Simultaneous Phenotyping of Human Cytochrome P450 Isoforms in Plasma, Saliva and Dried Blood Spots. Clin Pharmacokinet 53, 271–282 (2014). https://doi.org/10.1007/s40262-013-0115-0

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