Influence of albumin on the net sinusoidal efflux of the organic anion dibromosulfophthalein from rat liver

Nijssen, Henricus M. J.; Pijning, Tjaard; Meijer, Dirk K. F.; Groothuis, Geny M. M.

doi:10.1002/hep.1840150221

Cited by 12 publications

(14 citation statements)

References 20 publications

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“…This was shown for BSP [42] and DBSP [26]: in the absence of albu min the extraction is so high that in normal perfusions only zone-1 cells and in retro grade perfusions only zone-3 cells are ini tially involved in uptake and transport. However, normally in the presence of albu min the extraction is much lower and all aci nar cells are involved in transport of BSP…”

Section: Binding and Acinar Heterogeneitymentioning

confidence: 86%

“…However, if a gradient is demonstrated, het erogeneity in intracellular protein binding as well as biliary and sinusoidal excretion can be inferred from the kinetic data. In this case it should be checked that the acinar distribu tion does not change in time, for instance, due to sinusoidal excretion and reuptake in downstream cells as was demonstrated to occur with rhodamine B [18], dibromosulfophthalein (DBSP) [26], and parathione [27,28]. Reuptake by downstream cells of substrate excreted into the sinusoids, thus changing the acinar labelling, can be pre vented when, after loading one of the zones, the direction of perfusate flow is reversed ( fig.…”

Section: Isolated Perfused Rat Liver (Iprl) Techniquementioning

confidence: 99%

“…As most drugs and xenobiotics are more or less water-soluble com pounds, special precautions are necessary to Separation of Isolated Hépatocytes prevent diffusion of the compound during processing. For radioactive substrates a spe cial technique of freeze autoradiography can be successfully applied [22,25,33], For fluo rescent substrates the localization can be de tected on air-dried frozen sections using the fluorescence microscope [18,20,21,26,34], For the localization of transport of proteins, conventional autoradiography after fixation of the tissue can be applied for 125I-labelled proteins [12,35], Fluorescence microscopy for FITC-labelled proteins and (immuno)-histochemical techniques [36,37] can be ap plied. In some studies with bile acids, the bile acid was either derivatized with a tripep tide to be fixed [38,39] or with a fluorescent label to be detectable by fluorescent micros copy [40], but here it remains difficult to prove that the labelled substrates behave kinetically identically with the unlabelled sub strate.…”

Section: Localization Of Substrates In the Acinusmentioning

confidence: 99%

“…In some studies with bile acids, the bile acid was either derivatized with a tripep tide to be fixed [38,39] or with a fluorescent label to be detectable by fluorescent micros copy [40], but here it remains difficult to prove that the labelled substrates behave kinetically identically with the unlabelled sub strate. This may even be a problem with FITC-labelled proteins [41], Some substrates can be visualized by histochemical proce dures such as colloidal gold [34], bromosulfophthalein (BSP) [42], and DBSP [26].…”

Section: Localization Of Substrates In the Acinusmentioning

confidence: 99%

“…[25] and DBSP [26]. In addition, plasma protein binding accelerates the redistribu tion of DBSP, excreted from zone-1 cells back into the sinusoids, to the more distal zone-2 and zone-3 cells [26].…”

Section: -Oxmentioning

confidence: 99%

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Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

Groothuis¹,

Meijer²

1992

Enzyme

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In the past two decades many studies have been devoted to the involvement of the periportal (zone-1) and perivenous (zone-3) hepatocytes in bile formation and hepatobiliary transport of endogenous and exogenous compounds. It became clear that such a heterogeneity in transport function can, in principle, be due to the different localization of the cells in the acinus with respect to the incoming blood, to intrinsic differences between the cells or to both. In this review we first discuss the techniques used to study hepatocyte heterogeneity in hepatobiliary transport function. Combinations of such techniques can be used to discriminate between cellular heterogeneity due to acinar localization as opposed to intrinsic differences. These techniques include: normal and retrograde perfusions of isolated perfused livers; autoradiographic, fluorimetrie and histochemical localization of injected substrates; separation of isolated hepatocytes into fractions enriched in periportal and perivenous cells; measurements of fluorescent surface signals with microlight guides; selective zonal toxicity, and pharmacokinetic modelling and analysis. Subsequently, for each of the rate-limiting steps in the hepatobiliary transport of organic compounds, the basic mechanisms are summarized and the available knowledge on the involvement of the cells from the various zones in these transport steps is discussed. The available literature data indicate that heterogeneity in transport function is often due to the localization of the cells in the acinus: the periportal cells are the first to come into contact with the portal blood and are thus exposed to the highest substrate concentration. Consequently they obtain the most prominent task in further disposition of the particular compound. It follows that the extent of involvement of the perivenous cells in drug disposition is implicitly determined by the activity of the periportal cells. Because of the potential saturation of elimination processes in the periportal cells, the involvement of perivenous cells may vary with the input concentration. In addition, real intrinsic differences have been established in the hepatobiliary transport of some substrates. These are probably based on differences in the cellular content of carrier- and receptor-binding and/or metabolizing proteins. In some cases these intrinsic differences may be secondary to existing sinusoidal gradients of endogenous compounds, such as O(2), amino acids, bile acids or monosaccharides. Yet, data on the heterogeneity of hepatocytes in the various transport steps are far from complete or are even totally lacking, especially for human liver. A multi-experimental approach and advanced technology will be needed in the future to gain more insight into the acinar organization of bile formation and hepatobiliary transport of drugs in the human.

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Section: Binding and Acinar Heterogeneitymentioning

confidence: 86%

Section: Isolated Perfused Rat Liver (Iprl) Techniquementioning

confidence: 99%

Section: Localization Of Substrates In the Acinusmentioning

confidence: 99%

Section: Localization Of Substrates In the Acinusmentioning

confidence: 99%

Section: -Oxmentioning

confidence: 99%

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Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

Groothuis¹,

Meijer²

1992

Enzyme

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Hepatic Removal Kinetics: Importance for Quantitative Measurements of Liver Function

Keiding¹,

Sørensen²

2007

Textbook of Hepatology

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Pharmacokinetic modeling of the sinusoidal efflux of anionic ligands from the isolated perfused rat liver: The influence of albumin

Proost

Nijssen

Strating

et al. 1993

Journal of Pharmacokinetics and Biopharmaceutics

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This study contains a pharmacokinetic analysis on the efflux of organic anions from the liver into the bloodstream (sinusoidal efflux) with specific reference to the influence of albumin. The net sinusoidal efflux rate of dibromosulfophthalein (DBSP) from preloaded livers, being the resultant of sinusoidal efflux and reuptake of ligand by hepatocytes downstream the sinusoid, can be strongly increased by the presence of bovine serum albumin (BSA), a protein having multiple binding sites for DBSP. We previously attributed this effect to a reduction of reuptake through extracellular binding of the organic anion to the protein, rather than to an intrinsic stimulatory effect on the actual membrane transport process from the cells. In the present study we tested this hypothesis using a pharmacokinetic multicompartment liver model. This model resembles the parallel tube model in that the liver is described by several compartments placed in series instead of a single well-stirred compartment and it takes into account rates of dissociation and association in binding to proteins in the sinusoidal space. The model parameters were fitted from the sinusoidal efflux and biliary excretion data from efflux experiments measuring the stimulatory effect of various concentrations of BSA. Equilibrium binding of DBSP to albumin as well as the dissociation rate constant (koff) were determined in vitro with rapid filtration techniques. The experimental data could not be fitted satisfactorily when using the experimentally obtained values of the protein association and dissociation rate constants (kon and koff). However, they could be simulated accurately assuming 16 times higher values for the association and dissociation rate constant compared to those determined in vitro. Time constants of the perfusate flow, liver (re)uptake, and protein association and dissociation indicate that binding equilibrium does not exist within the sinusoids and that, in particular at low protein concentrations, the net sinusoidal efflux rate is association rate-limited: A large fraction of the ligand effluxed from the cell into the median is taken up by the hepatocyte before binding to the proteins occurs. Higher kon and koff values predicted by the model might indicate altered DBSP-albumin binding characteristics upon passage through the liver but alternatively can be explained by an intrinsic effect of albumin on the carrier-mediated efflux process. Efflux experiments showed a marked stimulatory effect of the protein on sinusoidal efflux but only a moderate effect on biliary excretion, despite a strong decrease in liver content. These patterns indicate that sinusoidal efflux and biliary excretion occur from two different intracellular compartments that equilibrate slowly.

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Influence of albumin on the net sinusoidal efflux of the organic anion dibromosulfophthalein from rat liver

Cited by 12 publications

References 20 publications

Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

Hepatic Removal Kinetics: Importance for Quantitative Measurements of Liver Function

Pharmacokinetic modeling of the sinusoidal efflux of anionic ligands from the isolated perfused rat liver: The influence of albumin

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