Variation in Hepatic Extraction Ratio with Unbound Drug Fraction: Discrimination Between Models of Hepatic Drug Elimination

Modeling of substrate elimination by the liver: Has the albumin receptor model superseded the well-stirred model?

“…These analyses of the taurocholate and rose bengal data have led us to surmise that data which support the rather complex albumin receptor model may equally well be explained in terms of the simpler well-stirred model. This is consistent with the general observation that the well-stirred model predicts a higher elimination rate than the parallel tube model, for a given concentration of unbound substrate (7,22). The converse does not apply, since experiments supporting the well-stirred model, involving perturbations of hepatic blood flow rather than unbound fraction of substrate (23)(24)(25), cannot be readily explained in terms of receptor-mediated uptake.…”

“…This limitation appears to have been recognized by Keiding and Priisholm (31) who recently repeated their earlier study of ethanol (28), but used an experimental design more appropriate for discriminating between the two models. Similarly, phenytoin was claimed to follow the well-stirred model (32), but the method used clearly does not discriminate (22). None of these studies (14, 15, 27-29, 32) attempted to fit the alternate model to their data.…”

Editorial II

“…Capacity-limited, but binding-sensitive hepatic elimination (for example digitoxin, mexilitine, midazolam, erythromycin, and tolbutamide) Usually these drugs show low intrinsic clearances, but high plasma protein binding (>85%), although there are some drugs with a large hepatic intrinsic clearance despite very high binding to plasma proteins. 13 It is dif®cult to generalize on the effects of liver dysfunction on the elimination of drugs in this group.…”

Effect of Altered Tissue Binding on the Disposition of Barbital in the Isolated Perfused Rat Liver: Application of the Axial Dispersion Model

“…Such studies have been employed to discriminate among the various models of hepatic drug elimination. [3][4][5][6][7][8][9] Several investigators have explored various aspects of altered tissue binding on hepatic disposition kinetics of drugs. [10][11][12][13][14][15] Nevertheless, study on the appropriateness of a model of hepatic clearance to accommodate changes in tissue binding remains challenging.…”