Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots.
The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
M
M
Bosilkovska
1] Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland [2] Swiss Center for Applied Human Toxicology, Geneva, Switzerland.
C F
CF
Samer
Unit of Toxicology, University Center of Legal Medicine, Geneva, Switzerland.
J
J
Déglon
Department of Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland.
M
M
Rebsamen
Unit of Toxicology, University Center of Legal Medicine, Geneva, Switzerland.
C
C
Staub
1] Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland [2] Swiss Center for Applied Human Toxicology, Geneva, Switzerland.
P
P
Dayer
Division of Anesthesiology, Geneva University Hospitals, Geneva, Switzerland.
B
B
Walder
1] Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland [2] Swiss Center for Applied Human Toxicology, Geneva, Switzerland.
J A
JA
Desmeules
1] Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland [2] Swiss Center for Applied Human Toxicology, Geneva, Switzerland.
Y
Y
Daali
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000097:blood*; D000284:Administration, Oral; D000328:Adult; D016642:Bupropion / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002214:Capsules; D002253:Carbonated Beverages; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D003069:Coffee; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000097:blood*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D059788:Dried Blood Spot Testing; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005240:Feasibility Studies; D005480:Flurbiprofen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D009853:Omeprazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood*; D010641:Phenotype; D010865:Pilot Projects; D011237:Predictive Value of Tests; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002214:Capsules; D003069:Coffee; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D016642:Bupropion; D002110:Caffeine; D005480:Flurbiprofen; D003915:Dextromethorphan; D016593:Terfenadine; D003577:Cytochrome P-450 Enzyme System; C093230:fexofenadine; D009853:Omeprazole; D008874:Midazolam