The effect of indomethacin on hepatic drug-oxidizing capacity in the rat: Trimethadione and antipyrine metabolism as an indicator.

Abstract

In this study, trimethadione (TMO) and antipyrine were chosen as model drugs to investigate the extent of hepatic drug-oxidizing capacity. It was also studied whether pretreatment of rats with indomethacin affected the formation of antipyrine metabolite. Pretreatment with indomethacin in a dose of 5 mg/kg/d for 3 d did not change the serum half-life (T1/2), the total body clearance (CL), and the apparent volume of distribution (Vd) of TMO and antipyrine. However, in the rat treated with 8.5 mg/kg/d for 3 d of indomethacin, these parameters were significantly decreased as compared to controls except to Vd values in antipyrine kinetics in vivo. The contents of cytochrome P-450, and the activities of aminopyrine N-demethylase and aniline hydroxylase were not changed by 5 mg/kg/d for 3 d of indomethacin. However, in the rat treated with 8.5 mg/kg/d for 3 d of indomethacin, these enzyme activities were significantly decreased as compared to controls. The activities of heme oxygenase were significantly increased as compared to controls in the rat treated with 5 and 8.5 mg/kg/d for 3 d of indomethacin, in vitro. The excretions of 4-hydroxyantipyrine and 3-hydroxymethyl antipyrine were not changed in the rat treated with 8.5 mg/kg for 3 d of indomethacin as compared to controls, whereas the excretion of norantipyrine was significantly decreased. These results, together with the previous findings, indicate that indomethacin treatment inhibited N-demethylation pathway of TMO and antipyrine metabolism.