Abstract
The pharmacokinetics of nimodipine, following a single 16 mg/kg oral dose, was investigated in rabbits with hepatic failure induced by 0.5 mL/kg (mild), 1.0 mL/kg (moderate) and 2.0 mL/kg (severe) of carbon tetrachloride $(CCl_{4}$ : olive oil = 20 : 80, v/v). The plasma concentrations of nimodipine were determined by a high performance liquid chromatographic assay. The levels of sGOT and sGPT in rabbits with mild $(86.2{\pm}29.0\;and\;98.5{\pm}33.1\;unit/dL)$, moderate $(168.1{\pm}61.2\;and\;196.2{\pm}66.0\;unit/dL)$ and severe $(292.7{\pm}82.2\;and\;314.2{\pm}99.8\;unit/dL)$ hepatic failure were significantly increased compared to the control $(38.0{\pm}10.1\;and\;32.4{\pm}10.2\;unit/dL)$. The area under the plasma concentration-time curve (AUC) of nimodipine was significantly increased in mild $(131.7{\pm}28.1%)$, moderate $(168.8{\pm}32.8%)$ and severe $(204.6{\pm}58.3%)$ carbon tetrachloride-induced hepatic failure rabbits compared to the control (100%) rabbits. The volume of distribution $(V_{d})$ and the total body clearance $(CL_{t})$ of nimodipine were significantly decreased in all hepatic failure groups. The elimination rate constant $(K_{el})$ of nimodipine was significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. There was a correlation between sGOT (y= 1.01x+241, r=0.993) or sGPT (y=0.92x +243, r=0.997) value and the AUC of nimodipine in the rabbits with hepatic failure. These findings suggest that the hepatic metabolism of nimodipine was inhibited by carbon tetrachloride-induced hepatic failure rabbits, resulting in the decrese in $V_{d}$ and $CL_{t}$ of nimodipine in the rabbits with mild, moderate and severe hepatic failure.
