Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9

Abstract

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 6β-hydroxylase activities, with mean IC₅₀'s of 0.19 and 0.22 μM 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_μM in incubations containing 100_μ) tolbutamide. Sulphaphenazole (at concentrations of up to 100_μ) did not exhibit any significant inhibition of the other enzyme activities investigated.

4. Ketoconazole and sulphaphenazole are the respective selective inhibitors of P4503 A and 2C9. Ketoconazole at 1 _μM and sulphaphenazole at 10_μM can be used to establish the involvement of P4503A and 2C9 respectively in oxidative reactions in human liver microsomes.