Abstract

The main purpose of this study was to predict the efficacy, potency and sensitivity of meloxicam (a preferential cyclooxygenase-2 (COX-2) inhibitor) antipyretic effect by using a simple indirect response model in rat, evaluated by Brewer’s yeast induced model. The rats received 1, 3, 7 and 10 mg/kg of meloxicam, after subcutaneous (sc) injection of Brewer’s yeast. The plasma concentrations of meloxicam were determined by high performance liquid chromatography-ultraviolet (HPLC-UV) method. Rectal temperature (Ta) was measured for the assessment of the pharmacodynamic (PD) of the meloxicam. Before injection of yeast, basal fever mediator’s synthesis (prostaglandin E₂; PGE₂) is maintained by physiological mechanism to regulate body temperature which is described by a constant rate synthesis (K_syn) and a first order degradation of K_out. K_syn is calculated by the equation, K_syn = E₀ K_out, where E₀ is the baseline body temperature. After injection of yeast, the additional fever mediators’ synthesis is regulated by input rate (IR (t)). This process is governed by a first order rate constant (K_IN), which can be inhibited by meloxicam. The pharmacokinetic (PK) parameters showed dose proportionality, with a Vd (4124.52, 4236.73, 4657.15, and 5912.1 ml/kg), CL (78.55, 149.25, 1313.57, and 1519.41 ml/h/kg), and Cmax (84.72, 258.29, 547.74, and 617.85 ng/ml). Indirect response PD model (inhibitory E_max model), estimated K_IN (1.43, 0.63, 0.51, and 0.42 1/h), K_out (0.005, 0.008, 0.015, and 0.028 1/h), and K_syn (0.29, 0.42, 0.076, and 0.03 h); estimates for IC₅₀ (concentration of meloxicam in plasma eliciting half of maximum inhibition of IR(t) or K_IN) were 146.19, 379.51, 645.05, and 676.44 ng/ml of 1, 3, 7 and 10 mg/kg dose received by groups, respectively. This model appropriately describes the time course of pharmacological response to meloxicam to various doses, in terms of its mechanism of action and pharmacokinetics.

Key words: Brewer’s yeast, cyclo-oxygenase-2, fever mediators (PGE₂), meloxicam, pharmacokinetic/ pharmacodynamic modeling.