The absorption, distribution, metabolism and excretion study of radiolabelled meloxicam in sheep following trans-mucosal delivery

Summary

Various forms of surgical husbandry procedures are necessary in sheep under good animal husbandry practices.   Pain management, following surgical husbandry procedures is required and there is a need for non-steroidal anti-inflammatory drug (NSAID) therapy in sheep and currently but no NSAID is registered in Australia for use in sheep.  In addition NSAID therapy is currently administered by injection which is undesirable from an on-farm occupational health and safety risk minimisation and food safety perspective.

Meloxicam, an oxicam derivative, is a selective cyclooxygenase-2 inhibitor and potent NSAID.  It is used as a veterinary drug for dogs, cats, cattle, pigs and horses either as an injectable solution or oral suspension.  Buccal administration of specifically formulated medications can result in rapid absorption.  Comparison of the bioavailability of oral and buccal meloxicam formulations administered to sheep showed that high serum levels of meloxicam were detected within 8 minutes of buccal dosing.  These levels approximate reported therapeutic levels in other species.          

Metabolism studies in the target animal are required to permit an assessment of the quantity and nature of residues in food derived from animals treated with a veterinary drug, and should provide data on:the depletion of residues of concern from edible tissues of treated animals at varying times after drug administrationthe individual components, or residues, that comprise the residues of concern in edible tissuesthe residue(s) that can serve as a marker for analytical methods intended for compliance purposes (that is the monitoring of appropriate drug use)the ratio of marker residue to total radioactive residuesthe identification of a target tissue or tissues.

The GLP (Good Laboratory Practice) study described in this report investigated the disposition of meloxicam in sheep following a single buccal administration of a radiolabelled meloxicam formulation (10 mg [14C]meloxicam/mL) at the maximum proposed dose rate of 1 mg meloxicam per kg bodyweight.

The study was conducted in accordance with the appropriate test facility standard operating procedures and in compliance with national and international standards such as: The UK Good Laboratory Practice Regulations; OECD Principles of Good Laboratory Practice; OECD Guidelines for the Testing of Chemicals, Metabolism in Livestock; EC Commission Directive 2004/10/EC; VICH GL46; and the APVMA data guideline on metabolism and kinetics.

Sixteen sheep (eight male and eight female) were given a single administration of [thiazole-2-14C]meloxicam at the nominal dose rate of 1 mg/kg bodyweight (bw). Urine, faeces and cage wash samples were collected daily. One group of four sheep (two male and two female) were killed at each of the following time points: 4 hours, 4 days (96 hours), 8 days (192 hours) and 14 days (336 hours).  Tissues were taken post mortem for quantification and analysis.  Analysis of meloxicam in ovine tissues was performed using a validated liquid chromatography – tandem mass spectrometry (LC/MS/MS) method.  Residue identification using accurate mass full scan and product ion analyses was carried out on selected sheep tissue, urine and faeces samples to screen for the presence of 'typical' or 'predicted' metabolites.

Key findings

The study showed that the majority of the mean administered radioactivity was excreted in the faeces and urine.   Parent meloxicam was the most abundant residue, and it was detected in all tissues (liver, kidney, muscle, fat, and application site) for both male and female sheep.  As a result, meloxicam was selected as the marker residue.  The next most abundant residue resulting from biotransformation of meloxicam and identified in all tissue samples was the oxoacetic acid metabolite of meloxicam.  

This data has allowed the conduct of a residue decline study, the setting of a minimum residue limit and a withholding period for meat following treatment.