Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9.
1. The potential of ketoconazole and sulphaphenazole to inhibit specific P450 enzyme activities (1A2, 2A6, 2B6, 2C9/8, 2C19, 2D6, 2E1, 3A and 4A) was investigated using human liver microsomes. 2. Ketoconazole demonstrated an inhibitory effect on cyclosporine oxidase and testosterone 6 beta-hydroxylase activities, with mean IC50's of 0.19 and 0.22 microM respectively. Ketoconazole inhibition of the other P450 activities investigated was significantly less, as illustrated by IC50's of at least a magnitude higher. 3. Sulphaphenazole was shown to have an inhibitory effect on tolbutamide hydroxylase activity, with a mean IC50 of 0.8 microM in incubations containing 100 microM tolbutamide. Sulphaphenazole (at concentrations of up to 100 microM) did not exhibit any significant inhibition of the other enzyme activities investigated. 4. Ketoconazole and sulphaphenazole are the respective selective inhibitors of P4503A and 2C9. Ketoconazole at 1 microM and sulphaphenazole at 10 microM can be used to establish the involvement of P4503A and 2C9 respectively in oxidative reactions in human liver microsomes.
Baldwin
S J
SJ
Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, UK.
Bloomer
J C
JC
Smith
G J
GJ
Ayrton
A D
AD
Clarke
S E
SE
Chenery
R J
RJ
D001189:Aryl Hydrocarbon Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors; D013426:Sulfaphenazole / Q000494:pharmacology*; D014044:Tolbutamide / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D013426:Sulfaphenazole; D014044:Tolbutamide; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster; D007654:Ketoconazole