KETOCONAZOLE AND SULFAPHENAZOLE AS THE RESPECTIVE SELECTIVE INHIBITORS OF P4503A AND 2C9

1. The potential of ketoconazole and sulphaphenazole to inhibit specif ic P450 enzyme activities (1A2, 2A6, 2B6, 2C9/8, 2C19, 2D6, 2E1, 3A an d 4A) was investigated using human liver microsomes. 2. Ketoconazole d emonstrated an inhibitory effect on cyclosporine oxidase and testoster one 6 beta-hydroxylase activities, with mean IC50's of 0.19 and 0.22 m u M respectively. Ketoconazole inhibition of the other P450 activities investigated was significantly less, as illustrated by IC50's of at l east a magnitude higher. 3. Sulphaphenazole was shown to have an inhib itory effect on tolbutamide hydroxylase activity, with a mean IC50 of 0.8 mu M in incubations containing 100 mu M tolbutamide. Sulphaphenazo le (at concentrations of up to 100 mu M) did not exhibit any significa nt inhibition of the other enzyme activities investigated. 4. Ketocona zole and sulphaphenazole are the respective selective inhibitors of P4 503A and 2C9. Ketoconazole at 1 mu M and sulphaphenazole at 10 mu M ca n be used to establish the involvement of P4503A and 2C9 respectively in oxidative reactions in human liver microsomes.