RESUMO
The hepatic extraction of metoprolol is reduced in rats with bilateral ureter ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the effect of uremic substances on the hepatic metabolism of metoprolol in rats with BUL. The metabolic rate in the liver microsomes of BUL rats was similar to that in sham rats, and there was no significant difference between sham and BUL rats in the effect of the supernatant of liver homogenates on the metabolism. The rate of metabolism in the liver microsomes in the presence of the plasma of BUL rats was also similar to that in the presence of the plasma of sham rats. These findings indicated that uremic substances which accumulate in BUL rats do not directly inhibit the activity of CYP2D2, which is responsible for the metabolism of metoprolol in the rat liver.
Assuntos
Antagonistas Adrenérgicos beta/farmacocinética , Fígado/metabolismo , Metoprolol/farmacocinética , Uremia/metabolismo , Antagonistas Adrenérgicos beta/urina , Albuminas/metabolismo , Animais , Citosol/metabolismo , Globulinas/metabolismo , Ligadura , Masculino , Metoprolol/urina , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Potássio/farmacologia , Ligação Proteica , Ratos , Ratos Wistar , Ureter/fisiologiaRESUMO
We previously reported that a decrease in hepatic NADPH generation results in reduced hepatic first-pass clearance of propranolol in rats with bilateral ureteral ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the mechanisms responsible for the reduced NADPH generation in the supernatant of liver homogenates (SUP) obtained from rats with BUL. The NADPH generation in the SUP in the presence of NADP(+) was decreased in BUL rats as compared with control rats. After the addition of glucose-6-phosphate or 6-phosphogluconic acid, the increase in NADPH in the SUP of BUL rats was similar to that in control rats. The NADPH generation in the SUP after the addition of the ultrafiltrate of BUL rat SUP was smaller than that after the addition of the ultrafiltrate of control rat SUP. These findings suggest that the enzymatic activities in the pentose phosphate pathway were not decreased significantly in BUL rats, and that the decrease in the generation of NADPH in BUL rats was mainly caused by the decreased concentration of endogenous substrate(s) and/or the increased concentration of endogenous inhibitor(s) for the pentose phosphate pathway.