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

Previous studies showed two deviations from the predictions of the undistributed parallel tube model for hepatic uptake of substrates: a small deviation at high flows and a large deviation at low flows. We have examined whether these deviations could be described by a single correction factor. In cats anesthetized with pentobarbital, a hepatic venous long-circuit technique with an extracorporeal reservoir was used to vary portal flow and hepatic venous pressure, and allow repeated sampling of arterial, portal, and hepatic venous blood without depletion of the cat's blood volume. Hepatic uptake of ethanol was measured over a wide range of blood flows and when intrahepatic pressure was increased at low flows. This uptake could be described by the parallel tube model with a correction for hepatic blood flow: [Formula: see text]. In 22 cats, [Formula: see text], k = 0.021 ± 0.0015 when flow (F) was in millilitres per minute per 100 g liver, and Km = 150 ± 20 μM when ĉ is the log mean sinusoidal concentration. (1 − e−kF) represents the proportion of sinusoids perfused and metabolically active. A dynamic interpretation of this proportion is related to intermittency (derecruitment) of sinusoidal flow. Half the sinusoids were perfused at a flow of 33 mL/(min∙100 g liver) and the liver was essentially completely perfused (> 95%) at the normal flow of 150 mL/(min∙100 g liver). Derecruitment was not changed by raising hepatic venous pressure, and it was not related to hepatic venous resistance.Key words: liver circulation, ethanol metabolism, liver blood flow, sinusoidal perfusion, portal pressure.

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Effects of liver blood flow on hepatic uptake kinetics of galactose in anesthetized cats: parallel tube model

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-188 ◽

1987 ◽

Vol 65 (6) ◽

pp. 1193-1199 ◽

Cited By ~ 7

Author(s):

C. V. Greenway ◽

F. J. Burczynski

Keyword(s):

Blood Flow ◽

Steady State ◽

Hepatic Blood Flow ◽

Venous Blood ◽

Liver Blood Flow ◽

Control Flow ◽

Tube Model ◽

Blood Flows ◽

Parallel Tube ◽

Parallel Tube Model

Hepatic galactose uptake in cats anesthetized with pentobarbital was determined during (i) steady-state infusions at several doses, (ii) rapidly increasing infusion rates at different blood flows, and (iii) prolonged infusion of a single dose at different blood flows. The hepatic venous long-circuit technique was used to allow frequent sampling of arterial, portal, and hepatic venous blood without depletion of the animal's blood volume and to allow measurement and alteration of total hepatic blood flow. Uptake was shown to follow Michaelis–Menten kinetics and was consistent with the "parallel tube model." The kinetic parameters Vmax and Kmax could be determined under steady-state and nonsteady-state conditions and were independent of hepatic blood flow over the range 60–150% of control flow. Mean Vmax was 80 μmol/(min∙100 g liver) and mean Km was 215 μM. Vmax declined by 50% when flow was reduced to half normal. It is concluded that the parallel tube model can be used to describe and predict hepatic galactose kinetics in anesthetized cats, although other models may fit the data equally well.

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Effects of hepatic blood flow on hepatic ethanel kinetics measured in cats and predicted from the parallel tube model

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-117 ◽

1989 ◽

Vol 67 (7) ◽

pp. 728-733 ◽

Cited By ~ 7

Author(s):

C. V. Greenway

Keyword(s):

Blood Flow ◽

Hepatic Blood Flow ◽

Ethanol Concentration ◽

Hepatic Uptake ◽

Distributed Model ◽

Tube Model ◽

Logarithmic Mean ◽

Parallel Tube ◽

Predicted Values ◽

Parallel Tube Model

In cats anesthetized with pentobarbital, a long-circuit technique was used to measure hepatic blood flow while portal flow was varied from 0 to 300% of normal in random steps. Arterial, portal, and hepatic venous blood samples were analyzed for ethanol concentrations during continuous infusion of ethanol (20 μmol/(min∙kg body weight)) into the reservoir. Measured values for logarithmic mean sinusoidal ethanol concentration, hepatic venous ethanol concentration, hepatic ethanol uptake, and ethanol extraction were compared with the values predicted by the parallel tube model for hepatic uptake of substrates using Vmax and Km determined in each cat at the start of the experiment. Measured and predicted values were very similar at all blood flows above 65% control, but statistical regression analysis indicated a small but highly significant deviation of the measured values from the predicted values. At low flows, measured values of logarithmic mean sinusoidal and hepatic venous concentrations markedly exceeded the predicted values in most cats. The results indicate that the parallel tube model, which assumes all sinusoids are identical and equally perfused, provides a useful approximation for the effects of hepatic blood flow on hepatic ethanol kinetics except at low flows. However, there appears to be a significant degree of sinusoidal heterogeneity that results in a better fit to the distributed model. Our previously reported data for hepatic galactose uptake followed a similar pattern when reanalyzed in this more rigorous way.Key words: liver circulation, ethanol metabolism, sinusoidal heterogeneity, distributed model for hepatic uptake.

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