Hepatic extraction of chenodeoxycholic acid in dogs chronically intoxicated with dimethylnitrosamine

Abstract

The pharmacokinetics of chenodeoxycholic acid (CDCA) in hepatic dysfunction were evaluated by analyzing the plasma disappearance curves after simultaneous administration of [ 3H]- and [ 14C]-CDCA through the femoral and portal veins, respectively, in dogs chronically intoxicated with dimethylnitrosamine (DMN). The plasma concentration-time curve of intravenously administered [ 3H]-CDCA was best fitted to a three-exponential equation, while that of intraportally administered [ 14C]-CDCA was fitted to either a two- or a three-exponential equation. In the DMN-intoxicated dogs. significant decreases were observed in total body plasma clearance ( CL p), hepatic extraction ratio ( E H ) and apparent intrinsic clearance ( CL int) compared to those of the untreated (control) dogs. The hepatic blood flow ( Q H ), calculated from CL p, CL int and blood-to-plasma concentration ratio ( R B) according to the equation reported by Wilkinson and Shand [ Clin. Pharmac. Ther. 18, 377 (1975)], was reduced to approximately 70% in the DMN-intoxicated dogs compared to the control dogs. The bindings of CDCA to plasma and liver cytosol fraction were determined by equilibrium dialysis; no significant difference was observed in the unbound fraction between the DMN-treated and control dogs. By comparing both pharmacokinetic parameters obtained from intravenous and intraportal administration, the usefulness of the oral bile acid tolerance test was examined. From these findings, it was suggested that the decrease in the CL p of the DMN-intoxicated dogs was due to both the decrease in Q H and that in CL int, and that the decrease in CL int may be due not to an alteration of plasma or cytosol binding but to that of a carrier-mediated transport system. It is also suggested that the measurement of fasting plasma bile acid concentration or the oral bile acid tolerance test is more sensitive for the detection of hepatic dysfunction than the intravenous bile acid tolerance test.