Tenoxicam pharmacokinetics in rats: a population model

This study was designed to establish the in vivo relationship between tenoxicam disposition and changes in plasma protein binding measured as an unbound fraction in plasma (fu). Tenoxicam was administered as a bolus 5-mg/kg dose, and total plasma concentrations, plasma albumin percentage, and fu were examined in five groups of rats (uremia or anephric states were experimentally induced in four groups to decrease plasma protein levels). Albumin levels were significantly decreased in all experimentally altered groups with respect to control animals (p < 0.01). A two-compartment population pharmacokinetic model that includes the effect of fu on the kinetic parameters was proposed to describe tenoxicam plasma concentration profiles. Plasma clearance (CL) increased but not proportionally with fu. Apparent volume of distribution of the central compartment (V) was linearly related to changes in fu and intercompartmental clearance was not affected by altered plasma protein binding. Expressing pharmacokinetic parameters as a function of fu resulted in a three- and five-fold decrease in the variability associated with CL and V, respectively.