mobiflex and Uremia

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.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Male; Piroxicam; Protein Binding; Rats; Rats, Wistar; Serum Albumin; Uremia

Renal alterations, uraemia and nephrotic syndrome induced in experimental animals caused a reduction in the plasma albumin concentration of 25 and 30%, respectively. As a result of this decrease, the unbound fraction of tenoxicam in uraemic rats (0.06 +/- 0.02) and in anephric rats (0.11 +/- 0.08) increased with respect to the control group (0.03 +/- 0.004). The induced hypoalbuminaemia did not modify the blood to plasma concentration ratio. Both plasma clearance (CL) and apparent volume of distribution at steady-state (Vdss) rose significantly with the increase in the unbound fraction: (Vdss 55 +/- 6 mL (control rats); 69 +/- 12 mL (uraemic rats); 96 +/- 30 mL (anephric rats); CL = 7 +/- 1 mL h-1 (control rats); 12 +/- 4 mL h-1 (uraemic rats); 15 +/- 7 mL h-1 (anephric rats)). Tenoxicam elimination was found to be restrictive, with an extraction ratio less than 0.1 in the three groups. The induction of nephrotic syndrome was observed to have a significant effect on intrinsic metabolic activity, intrinsic clearance of tenoxicam being reduced by 30% in the anephric rats (161 +/- 38 mL h-1) with respect to the values obtained in the control group (228 +/- 22 mL h-1).

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Male; Models, Biological; Nephrectomy; Piroxicam; Protein Binding; Rats; Rats, Wistar; Serum Albumin; Uremia