ALTERNATIVE CONTINUOUS-INFUSION METHOD FOR ANALYSIS OF ENTEROHEPATIC CIRCULATION AND BILIARY-EXCRETION OF CEFIXIME IN THE RAT

The enterohepatic circulation and biliary excretion of cefixime during continuous infusion were evaluated in rats based on the recirculatory concept. The Laplace-transformed equations for the enterohepatic circulation according to this concept were derived by means of the combination of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula by means of a nonlinear regression program, MULTI(FILT), into which the fast inverse Laplace transform was incorporated. The optimum model was selected on the basis of Akaike's information criterion (AIC). The time course of drug accumulation in the bile during infusion starts with a relatively gentle slope and finally approaches the asymptote with a constant slope. The kinetic significance of this asymptote was explained using the time courses of the cumulative amount excreted into the bile of rats with bile duct cannulation. The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the excreted amount into the bite. The recovery ratio (F,) and the mean circulatory time (($) over bar t(c)) through a single pass of enterohepatic circulation were estimated to be 31.1% and 0.925 h, respectively. The recovery ratio (F-a) and the mean transit time (($) over bar t(a),) for the complicated process from the access to the bile duct into the systemic circulation such as transport through the bile duct, absorption from the intestinal tract, and transit through the portal system were 76.4% and 0.0231 h, respectively. The recovery ratio (F-b) and the mean transit time (tb) for the disposition process through the systemic circulation into the bile were 40.7% and 0.902 h, respectively.