Are all measures of liver Kpuu a function of FH, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance?

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, Kpuu, is a function of or related to the hepatic bioavailability for that drug, FH. According to the derivation for the well-stirred model, Kpuu can never exceed unity, can frequently be a function of hepatic blood flow, and is equivalent to the value of FH as determined following oral dosing. For the parallel tube model, Kpuu will not equal FH but will be a function of FH and will also never be a value greater than 1. When hepatic clearance is rate limited by basolateral transporters, Kpuu will be less than 1, and less than FH. 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 (Css · CL = CH,u · CLint). Calculations of Kpuu and FH 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 Kpuu is independent of hepatic extraction ratio and FH.