A multi-sinusoidal compartment model as an alternative to the dispersion model for hepatic extraction kinetic analysis

The analysis of hepatic availability or hepatic extraction ratio as a function of hepatic blood flow and intrinsic clearance is important to estimate first-pass effects and oral bioavailability for pre-systemically-eliminating drugs. The dispersion model can afford more accurate analysis of hepatic availability than the other conventional models (well-stirred model, parallel-tube model). However, the model is rather complicate. In the present study, a simpler model was derived by assuming the sinusoidal space in the liver as a number of well-stirred compartments sequentially connected through the hepatic blood flow (multi-sinusoidal compartment model). In comparison with the other models, this model demonstrated hepatic outflow profiles very similar to those obtained by the dispersion model. It gave a simpler equation for hepatic availability, and improved the inaccuracy of the well-stirred model or the parallel tube model. The number of compartments, around 3, for this model corresponded to the dispersion number, 0.33, which has been reported to give the best fit to the rat hepatic outflow in the dispersion model. Similarly, the number of compartments, around 5 corresponded to the dispersion number, 0.17, which has been reported to give the best fit to the human hepatic elimination kinetics in the dispersion model.