title: Evaluation of Mutual Drug-Drug Interaction within Geneva Cocktail for Cytochrome P450 Phenotyping using Innovative Dried Blood Sampling Method.
abstract: Cytochrome P450 (CYP) activity can be assessed using a 'cocktail' phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low-dose probes with a low-invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre-treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail. To further validate this cocktail, in this study, we have verified whether probe drugs contained in the latter cause mutual drug-drug interactions. In a randomized, four-way, Latin-square crossover study, 30 healthy volunteers received low-dose caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam (a previously validated combination with no mutual drug-drug interactions); fexofenadine alone; bupropion alone; or all seven drugs simultaneously (Geneva cocktail). Pharmacokinetic profiles of the probe drugs and their metabolites were determined in DBS samples using both conventional micropipette sampling and new microfluidic device allowing for self-sampling. The 90% confidence intervals for the geometric mean ratios of AUC metabolite/AUC probe for CYP probes administered alone or within Geneva cocktail fell within the 0.8-1.25 bioequivalence range indicating the absence of pharmacokinetic interaction. The same result was observed for the chosen phenotyping indices, that is metabolic ratios at 2 hr (CYP1A2, CYP3A) or 3 hr (CYP2B6, CYP2C9, CYP2C19, CYP2D6) post-cocktail administration. DBS sampling could successfully be performed using a new microfluidic device. In conclusion, Geneva cocktail combined with an innovative DBS sampling device can be used routinely as a test for simultaneous CYP phenotyping.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Marija
authors.initials: M
authors.lastname: Bosilkovska
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.|Swiss Center for Applied Human Toxicology, Geneva, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Samer
authors.affiliation: Unit of Toxicology, University Center of Legal Medicine, Geneva, Switzerland.|DBS System, Gland, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Déglon
authors.affiliation: Unit of Toxicology, University Center of Legal Medicine, Geneva, Switzerland.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Division of Anesthesiology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Walder
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.|Swiss Center for Applied Human Toxicology, Geneva, Switzerland.
authors.forename: Jules
authors.initials: J
authors.lastname: Desmeules
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.|Swiss Center for Applied Human Toxicology, Geneva, Switzerland.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
mesh_terms: D000293:Adolescent; D000328:Adult; D016642:Bupropion / Q000008:administration & dosage / Q000493:pharmacokinetics; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D059788:Dried Blood Spot Testing / Q000379:methods*; D004347:Drug Interactions; D005260:Female; D005480:Flurbiprofen / Q000008:administration & dosage / Q000493:pharmacokinetics; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D010641:Phenotype; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D016642:Bupropion; D002110:Caffeine; D005480:Flurbiprofen; D003915:Dextromethorphan; D016593:Terfenadine; D003577:Cytochrome P-450 Enzyme System; C093230:fexofenadine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C504573:CYP1A2 protein, human; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole; D008874:Midazolam