TY - JOUR T1 - Are there any experimental perfusion data that preferentially support the dispersion and parallel tube models over the well-stirred model of organ elimination? JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.090530 SP - dmd.120.090530 AU - Jasleen K. Sodhi AU - Hong-Jaan Wang AU - Leslie Z. Benet Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/04/17/dmd.120.090530.abstract N2 - In reviewing previously published isolated perfused rat liver studies, we find no experimental data for high clearance metabolized drugs that reasonably or unambiguously supports preference for the dispersion and parallel tube models versus the well-stirred model of organ elimination when only entering and exiting drug concentrations are available. It is likely that the investigators cited here may have been influenced by: 1) the unphysiologic aspects of the well-stirred model, which may have led them to undervalue the studies that directly test the various hepatic disposition models for high clearance drugs (for which model differences are the greatest); 2) experimental assumptions made in the last century that are no longer valid today, related to the predictability of in vivo outcomes from in vitro measures of drug elimination and the influence of albumin in hepatic drug uptake; and 3) a lack of critical review of previously reported experimental studies, resulting in inappropriate interpretation of the available experimental data. The number of papers investigating the theoretical aspects of the dispersion, parallel tube and well-stirred models of hepatic elimination greatly outnumber the papers that actually examine the experimental evidence available to substantiate these models. When all experimental studies that measure organ elimination using entering and exiting drug concentrations at steady state are critically reviewed, the simple but unphysiologic well-stirred model is the only model that can describe all trustworthy published available data.SIGNIFICANCE STATEMENT Although the dispersion model of hepatic elimination more adequately reflects physiologic reality, there are no convincing experimental data that unambiguously favor this model. The well-stirred model can describe all well-designed perfusion studies with high clearance drugs and non-drug substrates, but the field has not recognized this due to hesitation to accept a non-physiologic model and flawed attempts to utilize IVIVE approaches. ER -