Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

Abstract

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drugs (for which model differences are the greatest); 2) experimental assumptions made in the last century that are no longer valid today, related to the predictability of in vivo outcomes from in vitro measures of drug elimination and the influence of albumin in hepatic drug uptake; and 3)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.

There is Only One Valid Definition of Clearance: Critical Examination of Clearance Concepts Reveals the Potential for Errors in Clinical Drug Dosing Decisions

“…Moreover, there was no paper in the literature critically reviewing those experimental studies. In our recent paper ( 12 ) “Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel Tube Models Over the Well-Stirred Model of Organ Elimination?” we conclude “Thus, in response to the title of this manuscript, we find no experimental data that reasonably or unambiguously support preference for the dispersion or parallel-tube models versus the well-stirred model of organ elimination when only entering and exiting drug concentrations are available. However, there are data that unambiguously show that C out / C in measurements with changing blood flow and protein binding can only be fit by the well-stirred model.”…”

“…The “reference concentration” approach implies there is a noncongruent second definition of clearance. Third, all IPRL experimental data measuring C in and C out appear to only fit the well-stirred model ( 12 ) .…”

Predicting human pharmacokinetics from preclinical data: absorption

“…In the case of F h , three models using CL int are so far known: well-stirred model, parallel tube model, and dispersion model. Although their performance in estimating F h is similar for many drugs, there is a report that the well-stirred model enormously overestimates the F h in a few drugs with F h lower than 10%, and the dispersion model appeared better at this situation [ 9 ]. The dispersion model assumes the concentration gradient from the capillary inlet to the outlet as in the parallel tube model and free diffusion of solutes along the blood flow axis [ 10 ].…”

Assessment of the Kochak-Benet Equation for Hepatic Clearance for the Parallel-Tube Model: Relevance of Classic Clearance Concepts in PK and PBPK

“…Preferable is application of such full mechanistic equations for the WSM and PTM that compare E H fittings as carried out by Pang and Rowland (8) who conceded that both models fitted some of these same data equally well (although the WSM was preferred for lidocaine). Such more proper comparisons have been done numerous times since (11). Kochak uses strong language to condemn the structure and operation of the WSM in advocating his version of the misinterpreted PTM.…”