Dispersion Model Of Hepatic Elimination Research Articles

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

In reviewing previously published isolated perfused rat liver studies, we find no experimental data for high-clearance metabolized drugs that reasonably or unambiguously support 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drugs (for which model differences are the greatest); 2) experimental assumptions made in the last century, which are no longer valid today, related to the predictability of in vivo outcomes from in vitro measures of drug elimination and the influence of albumin in hepatic drug uptake; and 3)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 nondrug substrates, but the field has not recognized this because of hesitation to accept a nonphysiologic model and flawed attempts to utilize in vitro-in vivo extrapolation approaches.

Correlation between in-vitro microsomal enzyme activity and whole organ hepatic elimination kinetics: analysis with a dispersion model.

A new model, the dispersion model of hepatic elimination, is applied to the correlation between in-vitro microsomal data and corresponding rat isolated perfused liver data for a number of drugs reported in the literature, whose extraction ratio varies over the range of 0.01 to 0.995. The dispersion model described the data better than either the 'well-stirred' model or the 'parallel-tube' model, two other widely used models of hepatic elimination. The experimental data support the concept that elimination of solutes is affected by is a considerable dispersion on passage through the liver.

A Two-compartment Dispersion Model Describes the Hepatic Outflow Profile of Diclofenac in the Presence of its Binding Protein

The residence-time distribution (RTD) of diclofenac in the rat single-pass isolated perfused in-situ liver (n = 4) was determined after bolus input into the hepatic portal vein. Addition of human serum albumin (5 g L-1) ensured extensive (greater than 98%) binding of diclofenac within the perfusate. The one-compartment form of the axial dispersion model of hepatic elimination, which assumes instantaneous radial distribution of substrate within the accessible spaces of the liver, failed to describe adequately the RTD of diclofenac. In contrast, the two-compartment form of this model, which assumes that the radial transfer of unbound substrate between the vascular and cellular space is non-instantaneous, provided an excellent description of the diclofenac data. Moreover, the mean (+/- s.d.) value for the hepatic dispersion number (DN) for diclofenac (0.354 +/- 0.076) compared well with that determined for simultaneously injected [125I]human serum albumin (0.456 +/- 0.078) using the one-compartment dispersion model. These estimates of DN, a stochastic parameter which characterizes the axial spreading of individual elements during transit through the liver, were similar in magnitude to those reported for other tracers in the rat perfused liver. The findings suggest that common factors influenced the RTD of diclofenac and its binding protein, and indicate that the two-compartment dispersion model may be a valuable tool for interpreting hepatic impulse-response data for solutes whose hepatic distribution and elimination is influenced by membrane permeability.

Optimal experimental design for precise estimation of the parameters of the axial dispersion model of hepatic elimination.

The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN, and the efficiency number, RN, corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.

Influence of Albumin on the Distribution and Elimination Kinetics of Diclofenac in the Isolated Perfused Rat Liver: Analysis by the Impulse-Response Technique and the Dispersion Model

The impulse-response technique was used to investigate the influence of changes in the perfusate concentration of human serum albumin (HSA; 1.5-25 g/L) on the distribution and elimination kinetics of [14C]diclofenac in the isolated perfused rat liver. Output data were analyzed by a linear systems approach in combination with the axial dispersion model of hepatic elimination. This stochastic model is characterized by a dimensionless parameter (the dispersion number, DN) that quantifies the relative spreading of a substance as it passes through the liver. The two-compartment form of the axial dispersion model, which assumes that the radial transfer of a substance between the vascular and cellular spaces proceeds at a finite rate, was used to describe the output profiles for diclofenac, thereby providing estimates for DN and the first-order rate constants for the transfer of drug between the vascular and cellular compartments (k12 and k21) and its sequestration from the cellular compartment (fc8l). With a change in perfusate HSA concentration, the only one of these parameters to alter significantly (analysis of variance, p < 0.05) was the uptake rate constant (k12), which increased from 0.091 ± 0.016 (mean ± standard deviation) to 0.79 ± 0.09s-1 as HSA decreased from 25 to 1.5 g/L. Most of this change could be accounted for by an increase in the fraction of diclofenac unbound in perfusate, from 0.0030 to 0.0407 as HSA decreased from 25 to 1.5 g/L. The relative magnitudes of k12, k21, and ke, suggest that although membrane permeability has an Important bearing on the distribution kinetics of diclofenac within the liver and therefore the shape of the output profile following an impulse input, the elimination of diclofenac is not subject to a hepatocyte membrane permeability limitation. The DN for diclofenac (0.3 to 0.4) was independent of protein concentration and was similar in magnitude to that determined for the noneliminated reference marker albumin. These results suggest that under conditions of high binding within the perfusion medium, the axial spreading of diclofenac within the liver is determined primarily by the heterogeneity of hepatic blood flow.

Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: 2. Effect of pharmacological agents, retrograde perfusions, and enzyme inhibition on evans blue, sucrose, water, and taurocholate

The effect of altered physiological conditions on the residence time distributions of sucrose, water, and taurocholate in the rat liver were studied using a bolus injection and quantifying fraction of total outflow per ml-time profiles. Retrograde perfusions increased the residence times of sucrose and water markedly and were associated with very low hepatic availabilities for taurocholate. Resistance by the inlet sinusoids sphincters, which become outlet sphincters during retrograde perfusions, is suggested as the explanation for the observation. Infusions of noradrenaline, propranolol, and lidocaine resulted in relatively small changes in the mean residence times for sucrose and water with no apparent relationship existing between the efficiency number of taurocholate and volumes of either water or sucrose. Taurochenodeoxycholate resulted in an increase in the availability and mean residence time for taurocholate relative to no infusion.

Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: 1. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate

The residence time distributions of sucrose and taurocholate have been determined from the outflow concentration-time profiles after bolus input into an in situ perfused rat liver preparation. The normalized variance (and the dispersion number) appeared to be independent of perfusate flow rate (10 to 37 ml/min) and perfusate albumin concentration (0.5%). The apparent volume of distribution for sucrose appeared to increase with flow rate but was unaffected by the concentration of albumin (0-5%) present in the perfusate. The changes in taurocholate availability with flow rate were adequately accounted for by the dispersion model, whereas taurocholate availability-protein binding changes required an albumin-mediated transport model to be used in conjunction with the dispersion model.

A dispersion model of hepatic elimination: 3. Application to metabolite formation and elimination kinetics.

A dispersion model of hepatic elimination is presented to describe metabolite formation and elimination kinetics within the liver, consistent with the known physiology and biochemistry of this organ. The model is based on the spread in residence times of blood flowing through the liver. This dispersion model is shown to be more consistent with transient and steady-state data obtained after the single passage of phenacetin and acetaminophen through the liver (both normal and retrograde perfusions) than other models of hepatic elimination. The dispersion model is suitable for the evaluation of enzyme heterogeneity using experimentally obtained metabolite data.

A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations.

A dispersion model of hepatic elimination, based on the residence time distribution of blood elements within the liver, is presented. The general rate equations appropriate for describing the hepatic output concentration of a tracer solute are derived. Particular consideration is given to events following a bolus input dose of a tracer. The model is shown to be compatible with the known hepatic architecture and hepatic physiology. The model has been fitted to hepatic outflow data for red blood cells, albumin, and other noneliminated solutes. The experimental data suggest a high degree of dispersion of blood elements within the liver. The model has also been used to evaluate the effects of changes in enzyme activity, hepatic cell permeability, blood flow, and protein binding on the outflow concentration vs. time profiles of solutes.

A dispersion model of hepatic elimination: 2. Steady-state considerations--influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity.

The dispersion model of hepatic elimination is based on the distribution of residence times of blood elements within the liver. The model has two asymptotic solutions corresponding to the "well-stirred" model (complete mixing of blood elements) and the "parallel-tube" model (no variation in residence times of blood elements). The steady-state form of the dispersion model relevant to pharmacokinetic analysis is developed and explored with respect to changes in blood flow, in binding within blood, and in hepatocellular enzyme activity. Literature data are used to evaluate discrepancies among the predictions of the dispersion, well-stirred, and tube models. It is concluded that the dispersion model is consistent with the data. The limitations of steady-state perfusion experiments to estimate the residence time distribution of blood elements within the liver are considered.

Intrahepatic distribution of hepatic blood flow: double-input studies

ARTICLESIntrahepatic distribution of hepatic blood flow: double-input studiesN Lifson, DG Levitt, Griffen WO Jr, and CJ EllisN Lifson, DG Levitt, Griffen WO Jr, and CJ EllisPublished Online:01 May 1970https://doi.org/10.1152/ajplegacy.1970.218.5.1480MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByBlood Flows in Tributaries of the Portal Vein: Anatomical and Angiographic Studies in Normal Beagle Dogs7 November 2014 | Anatomia, Histologia, Embryologia, Vol. 44, No. 6Heterogeneity of the intrahepatic portal venous blood flow: Impact on hepatocyte transplantationMicrovascular Research, Vol. 86PKQuest: volatile solutes – application to enflurane, nitrous oxide, halothane, methoxyflurane and toluene pharmacokinetics15 August 2002 | BMC Anesthesiology, Vol. 2, No. 1PKQuest: measurement of intestinal absorption and first pass metabolism – application to human ethanol pharmacokinetics15 August 2002 | BMC Clinical Pharmacology, Vol. 2, No. 1PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol15 August 2002 | BMC Clinical Pharmacology, Vol. 2, No. 1PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics26 September 2002 | BMC Clinical Pharmacology, Vol. 2, No. 1Dependency of the [18f]fluoromisonidazole uptake on oxygen delivery and tissue oxygenation in the porcine liverNuclear Medicine and Biology, Vol. 27, No. 8Use of a Two-Compartment Model to Assess the Pharmacokinetics of Human Ethanol MetabolismAlcoholism: Clinical and Experimental Research, Vol. 22, No. 8Measurement of liver blood flow using oxygen-15 labelled water and dynamic positron emission tomography: Limitations of model descriptionEuropean Journal of Nuclear Medicine, Vol. 23, No. 2Patterns of colorectal liver metastases according to Couinaud's segmentsDiseases of the Colon & Rectum, Vol. 38, No. 3Role of the hepatic artery in the metabolism of phenacetin and acetaminophen: An intravital microscopic and multiple-indicator dilution study in perfused rat liverHepatology, Vol. 20, No. 3Marked Heterogeneity in the Intrahepatic Distribution of Quinidine in Rats: Implications in PharmacokineticsJournal of Pharmaceutical Sciences, Vol. 79, No. 9Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: 1. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate1 June 1990 | Journal of Pharmacokinetics and Biopharmaceutics, Vol. 18, No. 3Liver blood flowGastroenterology, Vol. 81, No. 1Functional zones in rat liver: The degree of overlapJournal of Theoretical Biology, Vol. 89, No. 2Flow dependence of first-order uptake of substances by heterogeneous perfused organsJournal of Theoretical Biology, Vol. 86, No. 2Heterogeneity of macroscopic and single villus blood flow in rabbit small intestineMicrovascular Research, Vol. 17, No. 2The distribution of RB86 in different parts of the liverPfl�gers Archiv European Journal of Physiology, Vol. 346, No. 2 More from this issue > Volume 218Issue 5May 1970Pages 1480-1488 Copyright & PermissionsCopyright © 1970 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1970.218.5.1480PubMed5438277History Published online 1 May 1970 Published in print 1 May 1970 Metrics