Assessment of cytochrome P450 activity by a five-drug cocktail approach.
OBJECTIVE
Our goal was to establish and validate a modified cocktail approach including probe drugs caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam for simultaneous phenotyping of CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A.


METHODS
The study was conducted in 14 healthy, nonsmoking male volunteers with a cocktail of 5 drugs consisting of 100 mg caffeine, 200 mg chlorzoxazone, 100 mg mephenytoin, 100 mg metoprolol, and 7.5 mg midazolam in a randomized manner with a 7 x 7 Latin square design. Plasma was obtained at 1, 4, and 6 hours, and urine was collected from 0 to 8 hours after oral drug administration.


RESULTS
The phenotypic indexes determined for caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam were not significantly different when the drugs were given in different combinations. There were no metabolic interactions or analytic interference of these probe drugs.


CONCLUSIONS
This cocktail approach can simultaneously provide independent in vivo phenotypic measures for the cytochrome P450 (CYP) enzymes CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A.
Zhu
B
B
Pharmacogenetics Research Institute, Xiang-Ya School of Medicine, Central South University, Changsha, Hunan, China.
Ou-Yang
D S
DS
Chen
X P
XP
Huang
S L
SL
Tan
Z R
ZR
He
N
N
Zhou
H H
HH
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D002753:Chlorzoxazone / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008790:Metoprolol / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009853:Omeprazole / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; 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; D010089:Oxidoreductases, N-Demethylating; D008790:Metoprolol; D002753:Chlorzoxazone; D009853:Omeprazole; D008617:Mephenytoin; D008874:Midazolam