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Titolo:
PHARMACOKINETIC MODELING OF THE SINUSOIDAL EFFLUX OF ANIONIC LIGANDS FROM THE ISOLATED-PERFUSED RAT-LIVER - THE INFLUENCE OF ALBUMIN
Autore:
PROOST JH; NIJSSEN HMJ; STRATING CB; MEIJER DKF; GROOTHUIS GMM;
Indirizzi:
UNIV GRONINGEN,UNIV CTR PHARM,DEPT PHARMACOL & THERAPEUT,ANTONIUS DEUSINGLAAN 2 9713 AW GRONINGEN NETHERLANDS
Titolo Testata:
Journal of pharmacokinetics and biopharmaceutics
fascicolo: 4, volume: 21, anno: 1993,
pagine: 375 - 394
SICI:
0090-466X(1993)21:4<375:PMOTSE>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-SERUM ALBUMIN; HEPATIC TRANSPORT; MEDIATED TRANSPORT; ROSE-BENGAL; CONFORMATIONAL CHANGE; BILIARY-EXCRETION; BOUND SUBSTANCES; CELL-SURFACE; BILE-SALTS; BINDING;
Keywords:
PHARMACOKINETIC MODELING; SINUSOIDAL EFFLUX; DIBROMOSULFOPHTHALEIN; ALBUMIN; SERIES-COMPARTMENT MODEL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
55
Recensione:
Indirizzi per estratti:
Citazione:
J.H. Proost et al., "PHARMACOKINETIC MODELING OF THE SINUSOIDAL EFFLUX OF ANIONIC LIGANDS FROM THE ISOLATED-PERFUSED RAT-LIVER - THE INFLUENCE OF ALBUMIN", Journal of pharmacokinetics and biopharmaceutics, 21(4), 1993, pp. 375-394

Abstract

This study contains a pharmacokinetic analysis on the efflux of organic anions from the liver into the bloodstream (sinusoidal efflux) withspecific reference to the influence of albumin. The net sinusoidal efflux rate of dibromosulfophthalein (DBSP) from preloaded livers, beingthe resultant of sinusoidal efflux and reuptake of ligand by hepatocytes downstream the sinusoid, can be strongly increased by the presenceof 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, lather than to an intrinsic stimulatory effect on the actual membrane transport process from tire 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 (k(off)) 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 (k(on) and k(off)). 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 nod 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 medium is taken up by the hepatocytebefore binding to the proteins occurs. Higher k(on) and k(off) valuespredicted 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 ofthe 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 twodifferent intracellular compartments that equilibrate slowly.

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Documento generato il 19/09/20 alle ore 15:24:07