Differential inhibitory effects of phenytoin, diclofenac, phenylbutazone and a series of sulfonam ides on hepatic cytochrom e P4502C activity in vitro, and correlation with som e m olecular descriptors in the dwarf goat (Caprus hircus aegagrus).

Abstract

1. The aim of the present study was to investigate the potency of various sulfonamides to inhibit tolbutamide hydroxylation (a CYP2C activity) in hepatic microsomal fractions and hepatocytes of the dwarf goat. Also a number of suggested substrates for human CYP2C9 was investigated. 2. From Dixon plots (microsomal fractions) it was observed that all compounds were competitive inhibitors of tolbutamide hydroxylation. Phenytoin (PT) showed the lowest Ki. Ki for the sulfonamides ranged between 205 and 4546 μM, sulfadoxine having the lowest Ki followed by sulfadimethoxine, sulfamoxole, sulfadimidine and sulfaphenazole. 3. In hepatocytes sulfaphenazole and diclofenac were the most potent inhibitors. 4. Out data indicate that PT, diclofenac (DF) and phenylbutazone (PBZ) are relative strong competitive inhibitors of tolbutamide hydroxylation and they are probably also substrates for the same enzyme. Differential inhibition of tolbutamide hydroxylation by sulfonamides was observed. 5. Correlation of structural parameters with the inhibition constant or the inhibition in hepatocytes showed that molecular volume, polarisability and molecular surface area are important parameters in determining the rate of inhibition of tolbutamide hydroxylation by sulfonamides in both microsomes and hepatocytes. In addition, log Poct are also involved oct in determining inhibition constants in microsomal fractions.