Construction of a physiologically based pharmacokinetic model to describe the hepatobiliary excretion process of ligands: quantitative estimation of intracellular diffusion

Abstract

A physiologically based pharmacokinetic model was established to describe the hepatobiliary excretion process for ligands which are excreted into the bile without metabolic conversion. In this model, the following processes were taken into consideration: influx and efflux across the liver sinusoidal membrane, intracellular diffusion, and excretion across the canalicular membrane into the bile. The partial differential equation by which these processes were described was solved to obtain the Laplace transformed solution for the biliary excretion rate of ligands, based on the plasma concentration profiles as an input function. The time profiles for the biliary excretion rate of dibromosulfophthalein (DBSP; 6.80 mg/kg b.w.) or cefodizime (15.0 mg/kg b.w.) after i.v. bolus administration to rats were fitted to the solution using a nonlinear least-squares program based on a fast inverse Laplace transform (MULTI-FILT [Y. Yano et al., Chem. Pharm. Bull., 37, 1035 (1989)] to determine the permeability-surface area product across the plasma membrane as well as the apparent intracellular diffusion coefficient. DBSP and cefodizime were used as model compounds since these two ligands possess different binding characteristics for cytosol protein(s). Although both ligands are present predominantly in the cytosol, DBSP binds to intracellular protein(s) (such as ligandin) to a great extent whereas the protein binding of cefodizime is not so extensive. The fitted lines were superimposed on the experimental results.(ABSTRACT TRUNCATED AT 250 WORDS)