The effect of sulfaphenazole and sulfadoxine on tolbutamide disposition in dwarf goats ( Caprus hircus aegagrus)

Abstract

The aim of the present study was to investigate the effects of intravenously administered sulfadoxine (5 mg kg −1 bodyweight) or sulfaphenazole (5 mg kg −1 bodyweight) on the in vivo elimination of i.v. tolbutamide (5 mg kg −1 bodyweight), as both compounds were shown to inhibit tolbutamide hydroxylation in vitro. It was shown that relative large differences in tolbutamide clearance exist among goats (n = 6). A high correlation was seen between tolbutamide and sulfadoxine clearances. Tolbutamide clearance was significantly reduced by concommitant administration of sulfaphenazole. Sulfadoxine ( sdx) had a less consistent effect. Mean tolbutamide plasma clearance was not significantly affected due to the fact that three animals showed an inhibition, whereas three others apparently did not respond. A negative correlation was found between the amount of N4-acetyl sdx in urine and the sdx clearance. Approximately 93 per cent of tolbutamide was bound to plasma proteins. However, there was no evidence for displacement of tolbutamide from its protein binding sites by sulfaphenazole or sulfadoxine. The results described in the present study confirm previous in vitro data obtained with goat hepatocytes. Although quantitative differences in inhibition exist between in vivo and in vitro results, hepatocytes are a good model to study potential drug-drug interactions at the level of biotransformation processes.