Effect of albumin on hepatic uptake of warfarin in normal and analbuminemic mutant rats: Analysis by multiple indicator dilution method

Tsao, Su Chin; Sugiyama, Yuichi; Sawada, Yasufumi; Nagase, Sumi; Iga, Tatsuji; Hanano, Manabu

doi:10.1007/bf01059283

Cited by 45 publications

(38 citation statements)

References 20 publications

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“…The mechanisms by which these risk factors increase the risk of WRN are not clear but seem to be related to higher INR after warfarinization. Since approximately 97% of warfarin becomes bound to plasma protein, primarily albumin, and the remaining 3% is the unbound fraction that exhibits pharmacologic effects and is metabolized and excreted from the body [11], hypoalbuminemia that results in a greater amount of the free form of warfarin may promote over-anticoagulation [12], [13]. Decreased metabolism of warfarin in the liver (combined with the reduction in production of coagulation factors in severe cases) and plasma volume expansion induced by CHF with resultant dilutional hypoalbuminemia may contribute to the development of WRN [14], [15].…”

Section: Discussionmentioning

confidence: 99%

The Occurrence of Warfarin-Related Nephropathy and Effects on Renal and Patient Outcomes in Korean Patients

Ahn

Yoon

et al. 2013

PLoS ONE

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BackgroundWarfarin-related nephropathy (WRN) is a recently described disease entity, in which excessive warfarinization (international normalized ratio (INR) >3.0) causes acute kidney injury. Previous reports regarding WRN included few Asian patients who might have differed from the western WRN patients in terms of genetic and environmental factors.MethodsDuring the period of March 2003 to December 2011, the data about a total of 1297 patients who had serum creatinine (sCr) level measured within 1 week after INR >3.0 and within 6 months before INR >3.0 was analyzed through the retrospective review of electronic medical records of a single tertiary hospital in Korea.ResultWRN developed in 19.3% of patients having excessive warfarinization. The incidence was higher in the chronic kidney disease (CKD) group than the non-CKD group. The risk of WRN increased as the basal serum albumin level decreased and was strongly associated with highest quartile serum AST level at post INR elevation and the presence of congestive heart failure. But the presence of atrial fibrillation was protective against the development of WRN. Neither the presence of CKD nor basal estimated glomerular filtration rate (eGFR) was an independent risk factor for WRN. Despite no difference in the basal sCr level, the sCr level was higher in patients with WRN than those without WRN after follow-up. The mortality rates were also higher in patients with WRN.ConclusionsWRN developed in 19.3% of patients having excessive warfarinization. A lower basal serum albumin, highest quartile serum AST level at post INR elevation, and congestive heart failure were associated with the occurrence of WRN. The development of WRN adversely affected renal and patient outcomes.

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Section: Discussionmentioning

confidence: 99%

The Occurrence of Warfarin-Related Nephropathy and Effects on Renal and Patient Outcomes in Korean Patients

Ahn

Yoon

et al. 2013

PLoS ONE

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“…The procedures are basically as reported (8). Wistar male rats (250-270 g) anesthetized with ether were used.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we applied the multiple-indicator dilution (MID) method, previously used chiefly for analyzing hepatic transport of low-M, substances (6)(7)(8)(9).…”

mentioning

confidence: 99%

Dynamic determination of kinetic parameters for the interaction between polypeptide hormones and cell-surface receptors in the perfused rat liver by the multiple-indicator dilution method.

Sato

Sugiyama

Sawada

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Hepatic elimination of epidermal growth factor (EGF) via receptor-mediated endocytosis was studied by a multiple-indicator dilution method in the isolated perfused rat liver, in which cell polarity and spatial organization are maintained. In this method EGF was given with inulin, an extracellular reference, as a bolus into the portal vein, and dilution curves of both compounds in the hepatic vein effluent were analyzed. Analysis of the dilution curve for EGF, compared with that for somatostatin, which showed no specific binding to isolated liver plasma membranes, resulted as follows: (i) both extraction ratio and distribution volume of '2MI-labeled EGF decreased as the injected amount of unlabeled EGF increased; (ii) the ratio plot [In (inulin/EGF) versus time] ofthe dilution curve for EGF exhibited an upward straight line initially for a short period of time (-10 sec), whereas the ratio plot [In (inulin/somatostatin) versus time] of somatostatin gradually decreased. The multiple-indicator dilution method was used for other peptides also. Insulin and glucagon, known to have hepatocyte receptors, behaved similarly to EGF in shape of their ratio plots. Thus, analysis of dilution curves can reveal whether or not the cell surface has receptors for certain peptides. In addition, the dilution curves for EGF at various doses (tracer 30 jag) were analyzed simultaneously based on a kinetic model incorporating the perfusion rate, the association rate constant of EGF to surface receptors (kon), the dissociation rate constant of EGF from the EGF-receptor complex (ko)9 and the sequestration rate constant ofthe complex. The kinetic parameters [the dissociation constant (Kd = kl/k,) and the number of surface receptors] calculated by this analysis were comparable with reported values obtained by in vitro direct binding measurements at equilibrium using liver homogenates. We conclude that the multiple-indicator dilution method is a good tool for analyzing the dynamics of peptide hormones-cell-surface receptor interaction under a condition in which spatial architecture of the liver is maintained.Many peptide hormones in the circulating blood are eliminated by the liver. Above all, for hormones taken up via receptor-mediated endocytosis, the liver is a major homeostatic regulator in controlling the concentration of peptide hormones in circulating blood (1-3).The interaction between peptide hormones and their specific receptors has been analyzed principally by in vitro studies with isolated or cultured hepatocytes (4) and liver plasma membranes (5). These systems, however, neither maintain cell polarity nor include ligand delivery by the blood flow, thus creating difficulty when the physiological significance of the peptide-receptor interaction is being experimentally evaluated. Use of the liver-perfusion method may effectively resolve this problem, because cell polarity and spatial architecture between hepatocytes and the capillary bed are maintained in this system. However, determination of the microscopic kinetic constan...

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“…The well-stirred and parallel-tube models offer straightforward analysis of steady-state kinetic data from perfusion experiments. [1][2][3][4][5][6] In contrast, the dispersion model [5][6][7][8][9][10][11] and the distribution model 5,6,[12][13][14][15] have been developed to explain the outflow time-profile following a pulse input. The dispersion model equations with flexible initial and boundary conditions can explain a variety of outflow drug kinetics at non-steady-state.…”

Section: Introductionmentioning

confidence: 99%

Analysis program based on finite element method, MULTI(FEM), for evaluation of dose‐dependent local disposition of drug in liver

Fukumura¹,

Yamaoka²,

Higashimori³

et al. 1999

Journal of Pharmaceutical Sciences

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A curve-fitting program based on the Finite Element Method, MULTI(FEM), was developed to model nonlinear local disposition of a drug in the liver under non-steady-state conditions. The program was written in FORTRAN on an IBM-compatible personal computer. The validity of MULTI(FEM) was confirmed by analyzing the outflow kinetics of oxacillin (a model drug) following a pulse input to isolated, perfused rat livers, according to both linear and nonlinear dispersion models. Four dose levels (300, 1000, 3000, and 5000 microg) of oxacillin were administered to observe the dose-dependency in the hepatic local disposition. First, the individual outflow time-profiles at the same dose were averaged, and the average time-profile was analyzed by MULTI(FEM) based on linear dispersion models to yield a single curve fit. The fitted parameters at each dose level were compared with parameters estimated using MULTI(FILT), a program based on fast inverse Laplace transform, to analyze linear pharmacokinetics. The estimated parameters by MULTI(FEM) were in good agreement with those by MULTI(FILT). The apparent elimination rate constant (ke) decreased with an increase in dose, whereas other parameters showed no discernible dependency on an increase of dose. Second, the average outflow time-profiles at the four dose levels were simultaneously analyzed by MULTI(FEM) based on dispersion models featuring Michaelis-Menten elimination. The outflow time-profiles of oxacillin were well approximated by a two-compartment dispersion model with central Michaelis-Menten elimination. The maximum elimination rate constant (Vmax) and the Michaelis constant (Km) were estimated to be 1520 microg/mL/min and 41.3 microg/mL, respectively. Thus, the capability of MULTI(FEM) was demonstrated in evaluating capacity-limited local disposition in the liver.

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Effect of albumin on hepatic uptake of warfarin in normal and analbuminemic mutant rats: Analysis by multiple indicator dilution method

Cited by 45 publications

References 20 publications

The Occurrence of Warfarin-Related Nephropathy and Effects on Renal and Patient Outcomes in Korean Patients

The Occurrence of Warfarin-Related Nephropathy and Effects on Renal and Patient Outcomes in Korean Patients

Dynamic determination of kinetic parameters for the interaction between polypeptide hormones and cell-surface receptors in the perfused rat liver by the multiple-indicator dilution method.

Analysis program based on finite element method, MULTI(FEM), for evaluation of dose‐dependent local disposition of drug in liver

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