Pharmacokinetics of acebutolol and its main metabolite, diacetolol after oral administration of acebutolol in rabbits with carbon tetrachloride-lnduced hepatic failure

Pharmacokinetic characteristics of acebutolol and its main metabolite, diacetolol, following a single 10 mg/kg oral dose, were investigated in rabbits with carbon tetrachloride-induced hepatic failure. Plasma concentrations of acebutolol and diacetolol were determined by a high performance liquid chromatography assay. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration (Cmax) of acebutolol were significantly increased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. The ratio of the diacetolol to total acebutolol in plasma (i.e., metabolite percentage rate) was significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Volume of distribution (Vd) and total body clearance (CLt) of acebutolol were significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Slope of terminal phase (β) of acebutolol was significantly decreased in hepatic failure rabbits. These findings suggest that the Vd, CLt and β of acebutolol were significantly decreased as a result of inhibition of the hepatic metabolism in moderate to severe hepatic failure rabbits. Therefore, dose adjustment may be necessary for acebutolol in hypertensive patients with hepatic damage.