Abstract:We examined the influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was significantly reduced, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentrationtime curve is significantly decreased in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G.
We have previously reported good correlations among serum aminotransferase (AST) activity, metabolic enzyme activity of CYPs, and total clearance (CL tot ) of probe drugs in rats with acute hepatic failure induced by CCl 4 . In this study, we searched for new biochemical indicators that correlate with hepatic function and tried to simulate appropriate drug dosage in chronic hepatic failure. Model rats were prepared by administration of CCl 4 (1 ml/kg, s.c., 3 times/week) and used at 48 h after the last administration. Serum albumin concentration was time-dependently decreased and correlated well with 3 major biologic determinants of drug clearance, hepatic blood flow (HBF), intrinsic clearance (CL int ), and the unbound fraction of drugs in plasma ( f p ) after intravenous administration of cyclophospamide, tolbutamide, zonisamide, and chlorzoxazone (as probe drugs for low hepatic extraction) and propanolol and lidocaine (as high-hepatic extraction drugs). By calculating these parameters based on prediction equations by the level of albumin, CL tot was obtained. As a result of having evaluated this model using administration of cyclosporin, there was a statistically significant relationship between predicted CL tot and observed CL tot . In conclusion, the value of serum albumin level is a useful parameter that correlates well with chronic hepatic function. We have shown that this quantitative administering design using serum albumin level can predict appropriate dosages of hepatic metabolizing drugs in chronic hepatic failure.
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