Development of the "Inje cocktail" for high-throughput evaluation of five human cytochrome P450 isoforms in vivo.
To develop and validate an in vivo cocktail method for high-throughput phenotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A, 12 healthy subjects received five probe drugs alone or simultaneously. The in vivo phenotyping index of CYP2C9, the ratio of 8 h urine concentration of losartan to its metabolite after a single administration of losartan, was not significantly different from that obtained using the five-drug cocktail. Similarly, the ratios of [omeprazole]/[5-hydroxyomeprazole] (CYP2C19) and [paraxanthine]/[caffeine] (CYP1A2) in 4 h plasma samples and the log ratio of [dextromethorphan]/[dextrorphan] (CYP2D6) in 8 h urine samples and the 4 h plasma concentrations of midazolam (CYP3A) after single administration or well-established three-drug cocktail of caffeine, omeprazole, and dextromethorphan were not significantly different from those after the new five-drug cocktail. In conclusion, the new five-drug cocktail regimen, named the "Inje cocktail," can be used as a tool to phenotype in vivo enzyme activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A with only 4 h blood sampling and 8 h urine collection following simultaneous administration of the five probe drugs.
Ryu
J Y
JY
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Korea.
Song
I S
IS
Sunwoo
Y E
YE
Shon
J H
JH
Liu
K H
KH
Cha
I J
IJ
Shin
J G
JG
D000284:Administration, Oral; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000097:blood / Q000652:urine; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects; D016014:Linear Models; D019808:Losartan / Q000008:administration & dosage / Q000097:blood / Q000652:urine; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000652:urine; D006899:Mixed Function Oxygenases / Q000235:genetics; D009853:Omeprazole / Q000008:administration & dosage / Q000097:blood / Q000652:urine; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012016:Reference Values; D013997:Time Factors
D007527:Isoenzymes; D002110:Caffeine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; 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; D019808:Losartan; D009853:Omeprazole; D008874:Midazolam