Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail".
BACKGROUND
Simultaneous administration of several probes enhances the utility of phenotyping, but poor specificity, side effects, and use of drugs not approved by the Food and Drug Administration limit the usefulness of prior phenotyping cocktails.


OBJECTIVE
To evaluate potential drug-drug interactions associated with use of a cocktail of caffeine, omeprazole, dextromethorphan, and midazolam for simultaneous phenotyping of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase.


METHODS
Twelve subjects received caffeine + dextromethorphan, omeprazole, and midazolam (each alone), and a cocktail of caffeine + dextromethorphan + omeprazole + midazolam. Blood samples were collected at 120 minutes for omeprazole and 5/-hydroxyomeprazole, and at 0, 5, 30, 60, 120, 240, 300, and 360 minutes for midazolam. Twelve-hour urine samples were collected for analysis of dextromethorphan, caffeine, and metabolites.


RESULTS
The median CYP1A2 metabolic ratio after administration of caffeine + dextromethorphan was not significantly different from that obtained with the cocktail (P = .84). Likewise, the median N-acetyltransferase-2, xanthine oxidase, and CYP2D6 metabolic ratios were not significantly different after cocktail administration (P = .977 for each N-acetyltransferase-2; P = .795 for xanthine oxidase; P = .75 for CYP2D6). The median CYP2C19 metabolic ratio after cocktail administration was not significantly different from that obtained after omeprazole administered alone (P = 1.000). Also, midazolam plasma clearance was not significantly different after cocktail administration compared with that after administration of midazolam alone (P = .708). The only side effect was sedation, which was associated with intravenous midazolam and occurred to a similar extent after both individual and cocktail phenotyping.


CONCLUSIONS
These results indicate no pharmacokinetic or pharmacodynamic interactions that would limit the utility of this phenotyping cocktail for simultaneous measurement of the activity of multiple drug-metabolizing enzymes.
Streetman
D S
DS
Clinical Pharmacology Research Center, Department of Medicine, Bassett Healthcare, Cooperstown, NY, USA. danstr@umich.edu
Bleakley
J F
JF
Kim
J S
JS
Nafziger
A N
AN
Leeder
J S
JS
Gaedigk
A
A
Gotschall
R
R
Kearns
G L
GL
Bertino
J S
JS
D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics; D000996:Antitussive Agents / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D014969:Xanthine Oxidase / Q000235:genetics* / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000897:Anti-Ulcer Agents; D000996:Antitussive Agents; D000697:Central Nervous System Stimulants; D004338:Drug Combinations; D006993:Hypnotics and Sedatives; D002110:Caffeine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D014969:Xanthine Oxidase; D010089:Oxidoreductases, N-Demethylating; D001191:Arylamine N-Acetyltransferase; D009853:Omeprazole; D008874:Midazolam