Analysis of Nonlinear Hepatic Clearance of a Cyclopentapeptide,BQ-123, with the Multiple Indicator Dilution Method Using the Dispersion Model

Purpose. To bridge in vitro, in situ and in vivo kinetic analyses of the hepatic clearance of a cyclopentapeptide, BQ-123, by using dispersion models that assume nonlinear pharmacokinetics. Methods. Rat livers were perfused by the multiple indicator dilution method with doses of BQ-123 ranging from 1-1000 g. The outflow dilution curves were fitted to a two-compartment dispersion model that was solved numerically by the finite difference method. Further, in vivo plasma concentrations of BQ-123 after bolus injection were analyzed with a hybrid physiological model that incorporates the hepatic dispersion model. Results. The calculated Michaelis-Menten constants (K_m = 12.0 M, V_max = 321 pmol/min/10⁶ cells, P_dif = 1.2 l/min/10⁶ cells) were comparable to those obtained previously from the in vitro isolated hepatocyte experiment (K_m = 9.5 M, V_max = 517 pmol/min/10⁶ cells, P_dif =1.1 l/min/10⁶ cells). The plasma concentrations of BQ-123 at doses of 1-25 mg/kg were explained well by the hybrid physiological model. Conclusions. These results suggest that carrier-mediated transport on the sinusoidal membrane was responsible for the in vivo hepatic elimination of BQ-123.