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 (Ksyn) and a first order degradation of Kout. Ksyn is calculated by the equation, Ksyn = E0 Kout, 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 (KIN), 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 Emax model), estimated KIN (1.43, 0.63, 0.51, and 0.42 1/h), Kout (0.005, 0.008, 0.015, and 0.028 1/h), and Ksyn (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 KIN) 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.
Highlights
Like other nonsteroidal anti-inflammatory drugs (NSAIDs), meloxicam has been extensively used for the treatment of rheumatoid arthritis (Chen et al, 2008), osteoarthritis (Chen et al, 2008), Alzheimer’s disease (Goverdhan et al, 2012) and cancer (Tsubouchi et al, 2000)
In vivo preclinical pharmacokinetic/pharmacodynamic (PK/PD) modeling is a powerful approach which determines the pharmacodynamic properties of a dosage regimen and explores the safe and effective dose for clinical use
Mean observed peak plasma concentrations of meloxicam was observed after 3 h of the drug administration in all groups with the values 84.72 ± 6.75, 258.29 ± 23.60, 547.74 ± 29.24 and 617.85 ± 55.05 ng/ml for 1, 3, 7 and 10 mg/kg, respectively
Summary
Like other nonsteroidal anti-inflammatory drugs (NSAIDs), meloxicam has been extensively used for the treatment of rheumatoid arthritis (Chen et al, 2008), osteoarthritis (Chen et al, 2008), Alzheimer’s disease (Goverdhan et al, 2012) and cancer (Tsubouchi et al, 2000). There is a less chance of cardiotoxicity, which may be caused by the selective COX-2 inhibitors (Engelhardt et al, 1995) This preferential inhibition on COX-2 isoform leads to decreased production of prostaglandins which has a crucial role in inflammation, pain, etc. Selection of effective and safe dose for a dosage regimen is very crucial for clinical use. In vivo preclinical pharmacokinetic (what drug dose to the body)/pharmacodynamic (what drug dose to the body) (PK/PD) modeling is a powerful approach which determines the pharmacodynamic properties of a dosage regimen and explores the safe and effective dose for clinical use. Limited insights on in vivo NSAIDs pharmacokinetics and pharmacodynamics (Toutain et al, 1994, 2001; Lees, 2003) are available, a few preclinical studies have been conducted to model blood or plasma concentration-time profiles. To the best of our knowledge, there are only a few reported studies on PK/PD modeling of meloxicam in cat (Giraudel et al, 2005) and pharmacokinetics and pharmacodynamic studies in piglets (Fosse et al, 2008), but till date, there is no modeling studies of meloxicam in rat model
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