Meloxicam: metabolic profile and biotransformation products in the rat

Abstract

1. The metabolic fate of 14C-labelled meloxicam was investigated in the urine and bile of rat following oral and intraduodenal administration. Structural elucidation of metabolites was performed by nuclear magnetic resonance, mass spectrometry (electron impact and fast atom bombardment). 2. A mean total of 76.3% 14C-radioactivity was recovered in urine over 96 h, with the remainder in the faeces. The metabolic pattern in the excreta was independent of dose (1 versus 10 mg/kg) and collection period (0-8 versus 24-48 h). In bile one of the main metabolites was absent. 3. Meloxicam underwent extensive metabolism with only small amounts of unchanged drug recovered in the urine (< 0.5%) or bile (4.5%). Principal routes of biotransformation were: oxidation of the 5-methyl group of the N-heteroaryl-carbamoyl side chain to yield the 5'-hydroxymethyl derivative (33% of metabolites in urine, 22% in bile) and the 5'-carboxy derivative (16% in urine, 49% in bile). Oxidative cleavage of the benzothiazine-ring yielded an oxamic acid metabolite in urine (23.5%), which was not present in bile. 4. The introduction of a methyl-group into the N-heteroaryl-carbamoyl side chain increased lipophilicity and facilitated metabolic excretion compared with structurally related compounds.

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

“…A comparison of the biotransformation pathways of the two oxicam derivatives, sudoxicam and meloxicam indicates that sudoxicam is metabolized to the thiohydantoic acid and thiourea metabolites. Incorporation of a methyl group at the 5-position of the thiazole ring in meloxicam results in extensive oxidation of the methyl group resulting in an alcohol metabolite that undergoes further oxidation to carboxylic acid analog [325]. Little to no oxidative ring opening of the thiazole moiety in meloxicam is observed in humans.…”

A mass spectrometric study on meloxicam metabolism in horses and the fungus Cunninghamella elegans, and the relevance of this microbial system as a model of drug metabolism in the horse

“…The ion trap was filled with helium gas and the MS 1 , MS 2 , MS 3 and MS 4 scan modes were used. The relative collision energy was optimized for each mass transition and ranged from 22% for MS 2 to 34% for MS 4 The wide band activation parameter was not used in these experiments.…”

“…1), resulting in 5 -hydroxymethylmeloxicam and 5 -carboxymeloxicam. These two metabolites have been detected both in vitro and in vivo in different species such as humans, [7,8] thoroughbred horses, [5,6] rats, [2,8] mice and minipigs. [8] In earlier publications, the biotransformation of meloxicam has been investigated by the use of radioactivity monitoring after administration of 14 C-labelled meloxicam [2,8] and high performance liquid chromatography (HPLC) in combination with ultraviolet diode array detection (UV-DAD) [2] or either triple quadrupole mass spectrometry (MS) [8] or ion trap MS. [5,6] Smith and Rosazza suggested that microorganisms could be used as models of metabolism of xenobiotic substances in mammals.…”

“…These two metabolites have been detected both in vitro and in vivo in different species such as humans, [7,8] thoroughbred horses, [5,6] rats, [2,8] mice and minipigs. [8] In earlier publications, the biotransformation of meloxicam has been investigated by the use of radioactivity monitoring after administration of 14 C-labelled meloxicam [2,8] and high performance liquid chromatography (HPLC) in combination with ultraviolet diode array detection (UV-DAD) [2] or either triple quadrupole mass spectrometry (MS) [8] or ion trap MS. [5,6] Smith and Rosazza suggested that microorganisms could be used as models of metabolism of xenobiotic substances in mammals. [9] Since then, filamentous fungi such as Cunninghamella elegans have been used both as a complementary in vitro model for drug metabolism [10,11] and to produce drug metabolites in amounts sufficient for complete structural confirmation [12,13] or further toxicological testing.…”

“…It is closely structurally related to other oxicams such as sudoxicam, piroxicam, isoxicam and tenoxicam [1] ; although the methyl group on the thiazolyl ring has facilitated its metabolism and hence resulted in a shorter half-life compared to those of the others. [2] NSAIDs are extensively used in veterinary medicine due to their anti-inflammatory, analgesic and antipyretic properties. [3] Meloxicam is one of the newest drugs in this group and it is prohibited in the sports of horse racing.…”