The basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots.
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.
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Massimiliano
M
Donzelli
Division of Clinical Pharmacology and Toxicology, Inselspital Bern, Bern, Switzerland.
Adrian
A
Derungs
Viollier AG, Allschwil, Switzerland.
Maria-Giovanna
MG
Serratore
Viollier AG, Allschwil, Switzerland.
Christoph
C
Noppen
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Lana
L
Nezic
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Stephan
S
Krähenbühl
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University of Basel, Basel, Switzerland. manuel.haschke@unibas.ch.|Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, Hebelstrasse 2, 4031, Basel, Switzerland. manuel.haschke@unibas.ch.
Manuel
M
Haschke
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D059788:Dried Blood Spot Testing / Q000379:methods*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010641:Phenotype; D012463:Saliva / Q000201:enzymology*; D013810:Therapeutic Equivalency; D055815:Young Adult
D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System