Kinetics of Hepatic Uptake of Unconjugated Bilirubin

1976 ◽  
Vol 51 (2) ◽  
pp. 169-176 ◽  
Author(s):  
G. Paumgartner ◽  
J. Reichen
Keyword(s):  
Sodium Taurocholate ◽  
Compartment Model ◽  
Hepatic Uptake ◽  
Uptake System ◽  
Multiple Indicator Dilution ◽  
Half Saturation Constant ◽  
Carrier Mediated Transport ◽  
Multiple Indicator ◽  
Uptake Velocity ◽  
Kinetics Of

1. The uptake of bilirubin was studied in the perfused rat liver by a multiple-indicator dilution technique employing the three-compartment model of Goresky. 2. The kinetics of hepatic bilirubin uptake could be described by the Michaelis—Menten equation. 3. The maximal uptake velocity (Vmax.) and the apparent half-saturation constant (Km) were 4·4 ± 0·5 nmol s−1 g−1 of liver and 58 ±16 nmol/g of liver respectively, indicating that the hepatic uptake system for bilirubin under normal conditions is operating far below saturation. 4. Sodium taurocholate did not compete with bilirubin for hepatic uptake. 5. These findings are consistent with the concept that carrier-mediated transport is responsible for hepatocellular uptake of bilirubin and that bilirubin and bile acids enter the hepatocyte via separate pathways.

Uptake of bile acids by perfused rat liver

1976 ◽  
Vol 231 (3) ◽  
pp. 734-742 ◽  
Author(s):  
J Reichen ◽  
G Paumgartner
Keyword(s):  
Bile Acids ◽  
Rat Liver ◽  
Chenodeoxycholic Acid ◽  
Competitive Inhibition ◽  
Compartment Model ◽  
Hepatic Uptake ◽  
Perfused Rat Liver ◽  
Multiple Indicator Dilution ◽  
Rapid Injection ◽  
Carrier Mediated Transport

The uptake of 14C-labeled cholic, taurocholic, and chenodeoxycholic acid by the perfused rat liver was studied to characterize the mechanism responsible for hepatic uptake of bile acids. A rapid-injection multiple indicator-dilution technique and the three-compartment model of Goresky were employed. The kinetics of hepatic uptake of the three bile acids could be described by the Michaelis-Menten equation. The maximal uptake velocities (Vmax) were 24.9 +/- 2.2 (mean +/- SD), 20.8 +/- 1.2, 1.2, and 11.4 +/- 0.9 nmol/s-g liver for cholic, taurocholic, and chenodeoxycholic acid, respectively. The corresponding apparent half-saturation constants (Km) were 526 +/- 125, 258 +/- 43, and 236 +/- 48 nmol/g liver. Competitive inhibition could be demonstrated between cholate and taurocholate as well as between cholate and chenodeoxycholate. Substitution of 94% of the Na+ in the perfusion medium decreased the Vmax and the apparent Km of taurocholate uptake by 68 and 55%, respectively. These findings are consistent with the hypothesis that bile acids are taken up into the hepatocyte by Na+-dependent carrier-mediated transport.

A linear method for determining liver sinusoidal and extravascular volumes

1963 ◽  
Vol 204 (4) ◽  
pp. 626-640 ◽  
Author(s):  
Carl A. Goresky
Keyword(s):  
Linear Method ◽  
Compartment Model ◽  
Model System ◽  
Indicator Dilution ◽  
Red Cell ◽  
Multiple Indicator Dilution ◽  
Two Compartment Model ◽  
Multiple Indicator ◽  
Extracellular Substances ◽  
Volumes Of Distribution

Multiple indicator dilution studies of the hepatic circulation in the dog were carried out using labeled red cells, albumin, inulin, sucrose, sodium, urea, water, and T-1824. The materials were completely recovered in the outflow. Concentrations were expressed as fractions of the injected mass. The outflow pattern of each of the substances was displaced relative to the red cell curve, showing a lower peak concentration and longer transit time. The displacement was largest for water and urea, least for albumin and T-1824, intermediate for inulin, sucrose, and sodium. The results were analyzed using a flow-limited linear two-compartment model system. The analysis yielded estimates of sinusoidal blood volume and of the extravascular volumes of distribution of the diffusible labels. Water and urea volumes agreed with the liver weights and this agreement was taken as validation of the method of analysis. Volumes calculated for the other presumably extracellular substances demonstrated that the rapidly available extracellular space diminishes with increase in the molecular weight of the substance.

Hepatic uptake of hippurate: a multiple-indicator dilution, perfused rat liver study

1998 ◽  
Vol 274 (1) ◽  
pp. G10-G20 ◽  
Author(s):  
Tsutomu Yoshimura ◽  
Andreas J. Schwab ◽  
Lei Tao ◽  
Ford Barker ◽  
K. Sandy Pang
Keyword(s):  
Benzoic Acid ◽  
Rat Liver ◽  
Hepatic Uptake ◽  
Indicator Dilution ◽  
Monocarboxylate Transporter ◽  
Maximal Velocity ◽  
Perfused Rat Liver ◽  
Hepatic Transport ◽  
Multiple Indicator Dilution ◽  
Multiple Indicator

The hepatic transport of hippuric acid (HA), a glycine-conjugated metabolite of benzoic acid that exhibits only modest plasma albumin binding (binding association constant of 2.1 × 103M−1), was studied in the single-pass perfused rat liver (12 ml/min), using the multiple indicator dilution (MID) technique. The venous recovery of [3H]HA on portal venous injection of a MID dose containing a mixture of a set of noneliminated reference indicators and [3H]HA revealed a survival fraction of unity, corroborating the lack of disappearance of bulk HA from plasma. When the outflow recovery was fitted to the barrier-limited model of Goresky et al. (C. A. Goresky, G. G. Bach, and B. E. Nadeau. J. Clin. Invest. 52: 991–1009, 1973), the derived influx ( P in S ) and efflux ( P out S ) permeability-surface area products were found to be dependent on the concentration of HA (1–930 μM); P in S and P out S were ∼3.5 times the plasma flow rate at low HA concentration, but decreased with increasing HA concentration. All values, however, greatly exceeded the expected contribution from passive diffusion, because the equilibrium distribution ratio of chloroform to buffer for HA was extremely low (0.0001 at pH 7.4). The tissue equilibrium partition coefficient ( P in/ P out, or ratio of influx to efflux rate constants, k 1/ k −1) was less than unity and decreased with concentration. The optimized apparent Michaelis-Menten constant and maximal velocity were 182 ± 60 μM and 12 ± 4 nmol ⋅ s−1 ⋅ g−1, respectively, for influx and 390 ± 190 μM and 29 ± 13 nmol ⋅ s−1 ⋅ g−1, respectively, for efflux. In the presence ofl-lactate (20 mM), however, P in S for the uptake of HA (174 ± 3 μM) was reduced. Benzoic acid (10–873 μM) was also effective in reducing hepatic uptake of HA (5.3 ± 0.9 μM). These interactions suggest that MCT2, the monocarboxylate transporter that mediates the hepatic uptake of lactate and other monocarboxylic acids, may be involved in HA transport.

Influence of phenobarbital on the hepatic handling of [3H]vitamin D3 in the dog

1986 ◽  
Vol 251 (5) ◽  
pp. G627-G635 ◽  
Author(s):  
M. Gascon-Barre ◽  
S. Vallieres ◽  
P. M. Huet
Keyword(s):  
Enzyme Induction ◽  
Vitamin D3 ◽  
Hepatic Clearance ◽  
Correlation Coefficients ◽  
Hepatic Uptake ◽  
Indicator Dilution ◽  
Strong Positive Correlation ◽  
Dihydroxyvitamin D3 ◽  
Multiple Indicator Dilution ◽  
Multiple Indicator

The effect of phenobarbital (PB) on the hepatic handling of vitamin D3 (D3) and its metabolism to 25-hydroxyvitamin D3 [25(OH)D3] was studied in eight mongrel dogs. The hepatic uptake and clearance of [3H]D3 were evaluated by the multiple indicator-dilution curve technique, and the formation of [3H]25(OH)D3 was evaluated by sampling the hepatic effluent. The hepatic enzyme induction was assessed in six dogs by the 14CO2 breath excretion test. The results show that the hepatic uptake of [3H]D3 was not significantly affected but that its hepatic clearance was significantly increased during PB treatment. The [3H]25(OH)D3 production was increased during PB administration by a factor of 3–5 times over the pre- or post-PB period. Evaluation of the enzyme induction produced by PB revealed that two of the dogs studied had a blunted response to PB; furthermore, these dogs were the only animals that showed no increase in [3H]25(OH)D3 production during PB treatment and that in the presence of similar serum PB, endogenous 25(OH)D3 and 1,25-dihydroxyvitamin D3 pools, and hepatic uptake and clearance of [3H]D3. Strong positive correlation coefficients were observed between the breath excretion of 14CO2 and the [3H]25(OH)D3 production during PB treatment, whereas no correlation was present in the absence of PB. These observations show that, in most animals, PB is accompanied by an increased hepatic clearance of [3H]D3 and by an increased production of [3H]25(OH)D3. The data obtained during the present study also show that the response to PB is heterogeneous and that some animals escaped PB-mediated enzyme induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Facilitation of hepatic uptake of phenol 3,6-dibromphthalein disulfonate by taurocholate.

1977 ◽  
Vol 232 (6) ◽  
pp. E560
Author(s):  
Y Marinovic ◽  
J C Glasinovic ◽  
B Semelle ◽  
J F Boivieux ◽  
S Erlinger
Keyword(s):  
Bile Acid ◽  
Initial Velocity ◽  
Bile Salts ◽  
Sodium Taurocholate ◽  
Hepatic Uptake ◽  
Disappearance Rate ◽  
Plasma Disappearance Rate ◽  
Common Site ◽  
Half Saturation Constant ◽  
Uptake Process

The influence of sodium taurocholate (TC) on the hepatic uptake of phenol 3,6-dibromphthalein disulfonate (dibromosulphophthalein, DBSP) was examined in the dog. Single injections of DBSP (7.5-83.3 mg-kg-1) were given intravenously and the initial velocity of uptake (V) of the dye was calculated from the plasma disappearance rate measured during the 1st 5 min. It was observed that: a) the initial velocity of uptake of DBSP increased with the dose (D) in a nonlinear way, a finding consistent with Michaelis-Menten kinetics; the maximal initial velocity of uptake (Vmax) was 7.5+/-1.0 (SD) mg-min-1-kg body wt-1, and the half-saturation constant (Kd) was 27.7+/-7.0 (SD) mg-kg-1; b) when a TC infusion was given prior to the DBSP injection, the initial disappearance of the dye was more rapid than in the absence of the bile acid; Vmax increased to 12.3+/-2.0 (SD) mg-min-1-kg-1 (P less than 0.001) and Kd increased to 50.3+/-12.8 (SD) mg-kg-1 (P less than 0.001). These results indicate that: 1) the uptake of DBSP by the liver cell is a saturable process; 2) TC increases both the Vmax, suggesting a facilitation of the uptake process, and the Kd, suggesting competition for a common site. This effect of TC on DBSP uptake is similar to the previously described effect of this bile salt on BSP excretion into bile and suggests an interaction of bile salts with the uptake process of dyes.

The initial uptake of copper by the liver in the dog

1968 ◽  
Vol 46 (5) ◽  
pp. 771-784 ◽  
Author(s):  
Carl A. Goresky ◽  
Thomas H. Holmes ◽  
Andrew Sass-Kortsak
Keyword(s):  
Plasma Concentrations ◽  
Hepatic Uptake ◽  
Constant Infusion ◽  
Multiple Indicator Dilution ◽  
Dog Plasma ◽  
Major Organ ◽  
Before And After ◽  
Multiple Indicator ◽  
Wet Weight ◽  
Initial Uptake

The initial uptake of 64Cu and serum and tissue copper levels were examined in the dog. Plasma disappearance curves, multiple indicator dilution studies of initial hepatic uptake, and constant infusion experiments were carried out, at various doses, before and after preloading with cupric acetate. Over a range of plasma concentrations of direct-reacting copper extending to levels far above those encountered under physiological circumstances, little evidence of saturation of the initial hepatic uptake was evident. The countertransport of labeled copper was produced by administering unlabeled copper. The tissue levels of copper in the liver of the normal dog were, unexpectedly, found to be comparatively high, to average 82 μg/g wet weight. Attempts to produce manyfold increases in this copper content by daily intravenous copper administration failed because the doses of copper which would have been necessary to produce the increases, doses which would not have caused major toxic effects in the rat, were lethal for the dog. This low tolerance for copper loading presumably reflects the preexisting high copper concentration in the liver, the major organ which takes up exogenously administered copper. The degree of preloading which could be achieved produced no perceptible change in initial hepatic uptake. The copper levels in the liver are of the order of those found in some patients with Wilson's disease. Despite this, none of the other abnormalities which characterize this disease have been encountered in dogs.

Influence of embolism and imipramine on kinetics of serotonin uptake by dog lung

1984 ◽  
Vol 56 (5) ◽  
pp. 1170-1177 ◽  
Author(s):  
D. A. Rickaby ◽  
C. A. Dawson ◽  
J. H. Linehan
Keyword(s):  
Endothelial Function ◽  
Kinetic Parameters ◽  
Surface Area ◽  
Serotonin Uptake ◽  
Uptake Mechanism ◽  
Multiple Indicator Dilution ◽  
Endothelial Surface ◽  
Multiple Indicator ◽  
Induced Changes ◽  
Kinetics Of

We previously presented a model from which the kinetic parameters Km and Vmax for serotonin uptake by the lung can be obtained from multiple indicator-dilution data. The purpose of the present study was to determine whether experimentally induced changes in lung endothelial function would be revealed in the kinetic parameters calculated using the model. In experiments using isolated dog lung lobes, embolization with 550-microns glass beads was used to reduce the vascular volume and perfused surface area. Imipramine was used to inhibit the serotonin uptake mechanism. In addition, we studied the influence of the vasodilator papaverine, which in previous studies had been used to block the serotonin-induced vasoconstriction. Embolization, imipramine, and papaverine all significantly reduced percentage uptake of serotonin. The kinetic analysis revealed a significant decrease in the maximum serotonin uptake rate (Vmax) with all three experimental manipulations. In addition, imipramine significantly increased Km. The results indicate that the kinetic parameters obtained from the model do respond to transport inhibition and changes in endothelial surface area, further supporting their usefulness as indexes of endothelial function.

Hepatic uptake of 3,5,3'-triiodothyronine: electrochemical driving forces

1992 ◽  
Vol 262 (6) ◽  
pp. G1104-G1112
Author(s):  
R. A. Weisiger ◽  
B. A. Luxon ◽  
R. R. Cavalieri
Keyword(s):  
Plasma Membrane ◽  
Active Transport ◽  
Driving Forces ◽  
Electrical Potential ◽  
Hepatic Uptake ◽  
Electrical Potential Difference ◽  
Multiple Indicator Dilution ◽  
Multiple Indicator ◽  
Basolateral Plasma Membrane ◽  
Uptake Process

We used the multiple indicator dilution technique to assess the electrochemical forces driving uptake of 3,5,3'-triiodo-L-thyronine (T3) across the basolateral plasma membrane in the single-pass perfused rat liver. With the use of 4 g/dl albumin solutions, the influx and efflux clearances were 0.020 +/- 0.005 and 0.0049 +/- 0.0017 (SE) ml.s-1.g liver-1, respectively, indicating that the total T3 concentration at equilibrium should be about four times greater in cytoplasm than in plasma. However, when the influx and efflux clearances were divided by the unbound (free) T3 concentration in the perfusate and cytosol, they were not different (3.76 +/- 0.26 vs. 4.30 +/- 0.38 ml.s-1.g liver-1), indicating that the uptake process does not generate a gradient of unbound T3 across the plasma membrane. To further test whether T3 uptake is driven by the electrical potential difference across the plasma membrane, liver cells were depolarized by isosmotic replacement of perfusate chloride with gluconate. There was no effect on uptake or efflux. To test whether uptake is coupled to influx of sodium, perfusate sodium was replaced with choline. Although there was a modest decline in both the influx and efflux clearances, there was no change in their ratio, as would be expected for sodium-coupled active transport. These results indicate that uptake of T3 across the basolateral hepatocyte membrane occurs by passive diffusion. We found no evidence to support concentrative, active transport by either electrogenic or sodium-coupled mechanisms.

In vivo indicator dilution kinetics of PAH transport in dog kidney

1989 ◽  
Vol 257 (1) ◽  
pp. F158-F158
Author(s):  
M. Silverman ◽  
C. Whiteside ◽  
C. J. Lumsden ◽  
H. Steinhart
Keyword(s):  
Renal Vein ◽  
Indicator Dilution ◽  
Dilution Technique ◽  
Physiological Conditions ◽  
Multiple Indicator Dilution ◽  
Dog Kidney ◽  
Multiple Indicator ◽  
Kinetics Of ◽  
Experimental Runs

Pages F255–F265: M. Silverman, C. Whiteside, C. J. Lumsden, and H. Steinhart. “In vivo indicator dilution kinetics of PAH transport in dog kidney.” Two important early studies of PAH transport in the kidney were carried out using the pulse-injection, multiple indicator dilution technique (MID). These references were overlooked in our citations. Page F261: the text should read “Probenecid is a known inhibitor of organic ion transport. Chinard et al. (35) noted that probenecid doses of 25 mg/kg body wt, when administered to dogs 20–30 min prior to an MID run, resulted in renal vein outflow curves for hippurate nearly identical to those of simultaneously injected creatinine. Figure 5 illustrates our control and experimental runs using probenecid as an inhibitor of [3H]PAH transport .” Page F263: the text should read “As Chinard showed in the earliest renal MID work on PAH known to us (36), the MID technique as used in this study has the advantage of allowing one to look at events occurring simultaneously at opposing nephron surfaces in the anesthetized dog, under nearly normal physiological conditions (see also Ref. 27).”

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