摘要：A pharmacokinetic analysis program based on a tank-in-series model, MULTI(TIS), was developed for the evaluation of dose-dependency in the local disposition of a drug. The program written in FORTRAN was constructed by expanding MULTI(RUNGE). The reliability of MULTI(TIS) was verified by analyzing the experimental data based on linear and nonlinear tank-in-series models. Linear one- and two-compartment tank-in-series models were adopted to analyze outflow time profiles in single-pass hepatic perfusion following a pulse input of 5'-deoxy-5-fluorouridine (DFUR). The estimated parameters agreed well with those by MULTI(FILT) which is widely used for linear kinetic analysis. The nonlinear models adopted were one-compartment model with Michaelis-Menten elimination and two-compartment models with Michaelis-Menten elimination from central and peripheral compartments. Oxacillin was used as a model drug, because time courses of oxacillin show a capacity-limited hepatic disposition following a pulse input in high doses to the liver (300, 1000, 3000 and 5000 μg). The hepatic recovery ratio (FH) of oxacillin increased with dose, whereas the mean transit time (t^-H) was almost constant. The maximum elimination rate constant (Vmax) and Michaelis constant (Km) of oxacillin were estimated to be 1980 μg/ml/min and 54.1 μg/ml, respectively. Thus, the reliability of MULTI(TIS) was demonstrated for the analysis of nonlinear local disposition, especially, capacity-limited elimination in the liver.
