Response to the commentary on "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?"

Abstract

Recently, Sugano commented on our above-titled publication stating that he was a reviewer for the paper. In the Acknowledgements, Sugano indicated that we "kindly suggested publishing the reviewer report as an article". What we had actually written was: "prior to accepting the [unidentified] reviewer's approach, however, we believe he/she would have to publish a paper justifying the methodology and proposing how in vivo clinical data could be analyzed with such methodology". We further explained the fallacy of the accepted mechanistic models of hepatic elimination in a subsequent manuscript titled "Pharmacokinetic theory must consider published experimental data", published online a month after the Sugano commentary became available -not in time for the author to review the full explanation before his commentary was published. Our above-titled publication makes no assumptions or discussions regarding how Kp_uu should be measured, the major topic of the Sugano paper. Here we detail why the commentary methodology is not relevant to our demonstration that the present mechanistic models of hepatic elimination all lead to the unlikely conclusion that Kp_uu cannot exceed unity and is related to F_H. We also detail why the Extended Clearance Model should not be used for in vitro-in vivo extrapolation.