Protein binding and hepatic clearance: Discrimination between models of hepatic clearance with diazepam, a drug of high intrinsic clearance, in the isolated perfused rat liver preparation

Abstract

The influence of protein binding on the extraction ratio, and availability, of diazepam has been examined in the single-pass isolated perfused rat liver preparation. Binding of diazepam was varied by adjusting the concentration of albumin in the perfusate. In the absence of binding the extraction ratio of diazepam was high, 0.93-0.995. Extraction decreased dramatically as the degree of binding was increased. The data are more consistent with the "parallel-tube" model than with the "well-stirred" model, two perfusion models that have been used to describe hepatic drug elimination.

A Two-compartment Dispersion Model Describes the Hepatic Outflow Profile of Diclofenac in the Presence of its Binding Protein

“…Perfusate was delivered to the liver at a constant rate of 15 mL min-I via a cannula inserted into the hepatic portal vein, and liver effluent was collected via a cannula inserted into the vena cava through the right atrium. By monitoring the hepatic extraction of diclofenac under steady-state conditions (constant infusion of diclofenac into the hepatic portal vein), it was found that the perfused rat liver preparation remained viable for at least 2 h (manuscript in preparation), which confirmed earlier findings in which similar liver perfusion techniques were used to measure drug extraction (Schary & Rowland 1983;Rowland et al 1984). Liver viability was also assessed by monitoring perfusate recovery and bile flow, and by visually examining the liver during, and at the completion of each experiment.…”

Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

“…The literature search resulted in identification of only four publications that performed IPRL studies for high clearance drugs [lidocaine (Pang and Rowland, 1977;Ahmad et al, 1983), meperidine (Ahmad et al, 1983) and propranolol (Jones et al, 1984 and1985)] in which model differentiation was possible. Four additional studies were identified for two high clearance non-drug substances [galactose (Keiding and Chiarantini, 1978) and taurocholate (Smallwood et al, 1988;Ching et al, 1989;Roberts et al, 1990)] and five studies for which the low clearance drugs, diazepam and diclofenac, were manipulated to behave like a high clearance drug by altering protein binding (Rowland et al, 1984;Ching et al, 1989;Hussein et al, 1993;Diaz-Garcia et al, 1992;Wang and Benet, 2019). All discussed publications are listed in Table 1.…”

“…The authors again do not directly evaluate the fit of experimental data with variable flow to the dispersion model as they do for the well-stirred model. There are three experimental IPRL clearance studies with the low hepatic clearance drug diazepam and one with diclofenac from the last century, where the drug has been manipulated to be high clearance in the absence of plasma proteins (Rowland et al, 1984;Ching et al, 1989;Diaz-Garcia et al, 1992;Hussein et al, 1993). One study demonstrates preference of diazepam for the parallel tube model (Rowland et al 1984) and the other three studies demonstrate preference of diazepam (Ching et al, 1989;Diaz-Garcia et al, 1992) and diclofenac (Hussein et al, 1993) for the axial dispersion model versus the well-stirred model.…”

Targeted Delivery of Hormones to Tissues by Plasma Proteins

“…Therefore, k,, = l o 8 M-ls-l. and at a physiological albumin concentration of lop4 M, the bilirubin-rat albumin reassociation rate is 10,000 s-l, a value that is log orders greater than the permeation rate constant ( k3) of bilirubin transport into liver. Other studies have concluded that dissociation-limited uptake of plasma protein-bound ligands by organs in vivo is either rare or not possible (72,219).…”