Kinetic analysis of albumin-mediated uptake of warfarin by perfused rat liver

Abstract

We previously found that the uptake of warfarin in the presence of albumin by perfused rat liver could not be explained simply by the unbound warfarin concentration. The aim of the present study is to develop a kinetic model to account for this albumin-mediated uptake of warfarin. Single circulation indicator dilution studies on warfarin uptake were carried out in the isolated perfused rat liver in the absence and presence of various concentrations of bovine serum albumin (BSA) in the perfusate. A distributed model was fitted to the dilution data and the estimates of the influx, efflux, and sequestration rate constants were obtained. The results showed that the predicted concentration of the unbound warfarin is not high enough to explain the observed uptake rate; the liver cell surface appears to reduce the binding affinity of warfarin for BSA to 1/20 of that observed in vitro. A kinetic model which considers the interaction between albumin and the liver cell surface was fitted to the uptake rates of warfarin over a wide range of BSA concentration. The model gave a dissociation constant of the cell surface for albumin of 160 microM, which is comparable with those reported by others for the hepatic extractions of free fatty acids and rose bengal. Based on this kinetic model, the contributions of the unbound and bound warfarin to its hepatic uptake were estimated, and the bound warfarin was found to contribute most in the physiological albumin concentration range.

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.

“…In the model-independent analysis, we calculated the extraction ratio (E) and the distribution volume (Vd) from the zero moment (AUC) and the first moment (AUMC) of the dilution curve (15,16).…”

“…When first-order kinetics hold true, the dilution curve of a tracer dose of the test substance was also analyzed according to the flow-limited distributed model proposed by Goresky et al (9,16,17). This analysis gave three rate constants, k1, k2, and k3, corresponding to influx, efflux, and sequestration rate constant, respectively.…”

Targeted Delivery of Hormones to Tissues by Plasma Proteins

“…The difference between the in vivo K, value and the in vitro K, value reflects enhanced dissociation from the protein-binding site, and this phenomenon has been termed "plasma proteinmediated transport" (PMT). The PMT phenomenon has been observed by a number of different laboratories (5, 7, 15,67,68,79,152,[260][261][262]280) in addition to those cited in Table 14.5.…”

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

“…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.…”