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Tenoxicam: acute dose-dependent disposition studies in rats
L G Lopez-Bustamante1, J I Troconiz, D Fos
1Dpto. Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Navarra, Pamplona, Spain.
Journal of Pharmaceutical Sciences
|August 1, 1993
Summary
Higher doses of tenoxicam in rats increased its volume of distribution and plasma clearance due to saturable protein binding. These pharmacokinetic changes were not explained by blood-to-plasma concentration ratios.
Area of Science:
- Pharmacology
- Drug Metabolism and Pharmacokinetics
- Toxicology
Background:
- Tenoxicam is a non-steroidal anti-inflammatory drug (NSAID) used for treating inflammatory conditions.
- Understanding the dose-dependent pharmacokinetics of NSAIDs is crucial for optimizing therapeutic efficacy and minimizing adverse effects.
- Previous studies have indicated potential non-linear pharmacokinetic behavior for some NSAIDs.
Purpose of the Study:
- To investigate the impact of varying single intravenous doses of tenoxicam on its pharmacokinetic profile in male Wistar rats.
- To elucidate the relationship between tenoxicam dosage and key pharmacokinetic parameters such as volume of distribution and plasma clearance.
- To explore the role of plasma protein binding saturation in dose-dependent tenoxicam pharmacokinetics.
Main Methods:
- Male Wistar rats were administered single intravenous bolus doses of tenoxicam at 2.5, 5, and 10 mg/kg.
- Pharmacokinetic parameters, including apparent volume of distribution at steady state (Vdss) and total plasma clearance (CL), were calculated.
- Plasma protein binding of tenoxicam was assessed, and the unbound fraction was determined at different total drug concentrations.
- Blood-to-plasma concentration ratios were evaluated for concentration independence.
Main Results:
- A dose-dependent increase in tenoxicam pharmacokinetics was observed, with Vdss and CL being 42% and 45% higher, respectively, at the 10 mg/kg dose compared to lower doses.
- Plasma protein binding of tenoxicam demonstrated saturability, leading to a 33% higher unbound fraction at a total plasma concentration of 36 mg/L (high dose group).
- The blood-to-plasma concentration ratio remained concentration-independent, indicating it did not contribute to the observed dose-dependent changes in Vdss and CL.
Conclusions:
- Tenoxicam exhibits dose-dependent pharmacokinetics in rats, characterized by increased volume of distribution and plasma clearance at higher doses.
- Saturable plasma protein binding is a significant factor contributing to the non-linear pharmacokinetic behavior of tenoxicam.
- These findings highlight the importance of considering dose-dependent protein binding when assessing tenoxicam pharmacokinetics and determining appropriate dosing regimens.