UCSF

Here we present, utilizing universally accepted relationships for hepatic clearance at steady state, that for all models of hepatic elimination the ratio of unbound liver drug concentration to unbound systemic blood concentration, Kp_uu, is a function of or related to the hepatic bioavailability for that drug, F_H. According to the derivation for the well-stirred model, Kp_uu can never exceed unity, can frequently be a function of hepatic blood flow, and is equivalent to the value of F_H as determined following oral dosing. For the parallel tube model, Kp_uu will not equal F_H but will be a function of F_H and will also never be a value greater than 1. When hepatic clearance is rate limited by basolateral transporters, Kp_uu will be less than 1, and less than F_H. We believe that such outcomes are highly unlikely, and that the error arises from a basic assumption concerning hepatic clearance that leads to the mechanistic models of hepatic elimination, the well-stirred, parallel tube and dispersion models. That basic assumption is that the steady-state systemic concentration multiplied by the hepatic systemic clearance is equal to the product of the average unbound liver steady-state concentration and the intrinsic hepatic clearance (C_ss · CL = C_H,u · CL_int). Calculations of Kp_uu and F_H based on present methods of analysis provide a strong argument as to why this universally accepted relationship is not correct. Alternatively, we have shown in recent publications that hepatic clearance may be adequately determined based on Kirchhoff's Laws where no assumption of the above equality concerning hepatic intrinsic clearance is required, and where Kp_uu is independent of hepatic extraction ratio and F_H.