Evaluation of protein binding effect on local disposition of oxacillin in rat liver by a two-compartment dispersion model

Abstract

The effect of protein binding upon the hepatic uptake of oxacillin was evaluated in the rat isolated perfused liver, based on the two-compartment dispersion model by means of the fast inverse Laplace transform (FILT). The perfusion experiment was carried out using the perfusates without and with bovine serum albumin (BSA, 40 g L-1). Oxacillin was injected as a pulse through the portal vein, and the outflow concentration-time course of oxacillin was fitted to the dispersion model using the non-linear least squares program MULTI(FILT). The partition ratio (k'), which is the measure of the extent of the reversible distribution into the hepatic tissue, was 0.163 +/- 0.041 (s.d.) in the presence of BSA, and 0.095 +/- 0.018 in the absence of BSA, which suggests interaction of the albumin-bound drug with the hepatic tissue. The elimination rate constant (ke) from the perfusate in the absence of BSA was 8.0 +/- 0.55 min-1 and that in the presence of BSA was 3.3 +/- 1.4 min-1 while the unbound fraction of the drug in the presence of 40 g L-1 BSA was 0.282. The hepatic elimination rate of oxacillin was not proportional to the unbound concentration of drug suggesting hepatic uptake of the bound fraction.