Modelling and simulation of the nonlinear dose-plasma concentration response of phenylbutazone on periodic multiple oral dosing: A mechanistic approach

Abstract

The dose-ranging pharmacokinetics of phenylbutazone on periodic multiple oral dosing have previously been shown to be nonlinear, inasmuch as there is a plateauing of steady-state plasma concentrations with increasing dose. The mechanistic hypothesis of saturable protein binding, postulated to explain this behaviour was tested, in the context of whole-body pharmacokinetic modelling of the observed dose dependancy, using the circuit simulation program SPICE2. The alternate hypothesis, operating singly or in tandem, of loss of unabsorbed drug due to gastrointestinal emptying, saturable absorption, change in the volume of distribution of the drug, were also examined. Within the constraints of the proposed whole-body pharmacokinetic model, the absorption kinetics of increasing oral daily doses of phenylbutazone were shown to be saturable in their mechanism.