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Tenoxicam pharmacokinetics in rats: a population model
I F Troconiz1, L G Lopez-Bustamante, D Fos
1Department of Pharmacology, School of Medicine, University of Basque Country, Leioa, Spain.
Journal of Pharmaceutical Sciences
|December 1, 1995
Summary
This study shows that changes in plasma protein binding, measured as unbound fraction (fu), significantly impact tenoxicam disposition in rats. Accounting for fu in pharmacokinetic models reduces variability in clearance and volume of distribution.
Area of Science:
- Pharmacology
- Pharmacokinetics
- Drug Metabolism
Background:
- Plasma protein binding influences drug disposition.
- Understanding the unbound fraction (fu) is crucial for accurate pharmacokinetic modeling.
- Tenoxicam's disposition may be affected by altered protein binding.
Purpose of the Study:
- To establish the in vivo relationship between tenoxicam disposition and plasma protein binding (fu) in rats.
- To develop a pharmacokinetic model incorporating the effect of fu on tenoxicam kinetics.
- To assess the impact of altered plasma protein levels on tenoxicam's pharmacokinetic parameters.
Main Methods:
- Administered a 5-mg/kg bolus dose of tenoxicam to rats.
- Experimentally induced uremic or anephric states to reduce plasma protein levels.
- Measured total plasma concentrations, plasma albumin percentage, and unbound fraction (fu).
- Developed a two-compartment population pharmacokinetic model.
Main Results:
- Albumin levels were significantly decreased in experimental groups compared to controls (p < 0.01).
- Plasma clearance (CL) increased with fu, but not proportionally.
- Apparent volume of distribution of the central compartment (V) showed a linear relationship with fu.
- Intercompartmental clearance was unaffected by altered plasma protein binding.
- Incorporating fu reduced variability in CL by three-fold and in V by five-fold.
Conclusions:
- Plasma protein binding significantly influences tenoxicam pharmacokinetics in rats.
- A pharmacokinetic model accounting for unbound fraction (fu) improves the description of tenoxicam disposition.
- Accounting for fu in pharmacokinetic models enhances the predictability and reduces variability of drug parameters like clearance and volume of distribution.