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

Abstract

This paper describes a study where the metabolism of the non-steroidal anti-inflammatory drug meloxicam was investigated in six horses and in the filamentous fungus Cunninghamella elegans. The metabolites identified were compared between the species, and then the fungus was used to produce larger amounts of the metabolites for future use as reference material. C. elegans proved to be a good model of phase I meloxicam metabolism in horses since all four metabolites found were the same in both species. Apart from the two main metabolites, 5'-hydroxymethylmeloxicam and 5'-carboxymeloxicam, a second isomer of hydroxymeloxicam and dihydroxylated meloxicam were detected for the first time in horse urine and the microbial incubations. Phase II metabolites were not discovered in the C. elegans samples but hydroxymeloxicam glucuronide was detected intact in horse urine for the first time in this study. Urine from six horses was further analyzed in a semi-quantitative sense and 5'-hydroxymethylmeloxicam gave peaks with much higher intensity compared to the parent drug and the other metabolites, and was detected for at least 14 days after the last given dose in some of the horses. From the results presented in this article, we suggest that analytical methods developed for the detection of meloxicam in horse urine after prohibited use should focus on the 5'-hydroxymethyl metabolite and that C. elegans can be used to produce large amounts of this metabolite for potential future use as a reference compound.

Efficient biotransformation of non-steroid anti-inflammatory drugs by endophytic and epiphytic fungi from dried leaves of a medicinal plant, Plantago lanceolata L.

“…Nine of these metabolites were shown to be either mono-, or dihydroxy derivatives of the original anti-inflammatory drug molecules. The products generated by the fungi of the current study are similar to those found in the phase I metabolism of mammalsmetabolism to various hydroxylated products was shown for these pharmaceuticals (Macdonald et al, 1991;Wing Lam et al, 2007;Stülten et al, 2008;Tevell Åberg et al, 2009;Borges et al, 2010). These metabolites can be less toxic or more toxic compared to the original compounds.…”

Pharmacokinetics and Safety of Oral Administration of Meloxicam to Foals

“…Although clearance of NSAIDs is typically prolonged in foals/neonates, our findings are consistent with human pediatric studies, where the clearance of meloxicam was increased in juvenile patients . The metabolism and elimination of meloxicam by adult horses differs slightly from reports in other species, but in all species studied to date, the compound is metabolized by hepatic oxidation utilizing the cytochrome P450 2C subgroup to 4 principal, inactive metabolites, which are then excreted in urine and feces . As only very low levels of parent compound are present in urine, bile, or feces, meloxicam is evidently cleared almost exclusively by metabolism, and biotransformation governs elimination in all species studied to date .…”

Metabolic inhibition of meloxicam by specific CYP2C9 inhibitors in Cunninghamella blakesleeana NCIM 687: in silico and in vitro studies

“…The metabolite M1 formation from meloxicam was reported to mediate by cytochrome P450 2C9 with minor contribution of CYP3A4 enzyme in mammals (Chesne et al 1998). This derivative of meloxicam was also reported in Cunninghamella elegans, horses (Aberg et al 2009) and in C. blakesleeana NCIM 687 (Prasad et al 2009a). …”

“…This compound might be 5-carboxy meloxicam (M2). The production of metabolite M1 using C. elegans NCIM 690, Saccharomyces cerevisiae NCIM 3090, Bacillus subtilis MTCC 441, Pseudomonas putida NCIM 2783 and the production of both metabolites M1 and M2 using Aspergillus niger NCIM 589, A. ochraceous NCIM 1140, C.echinulata NCIM 691 was reported earlier (Prasad et al 2009a, b) and by Aberg et al (2009) in C. elegans and horses. These metabolites viz.…”

“…These metabolites viz. M1, M2 were also detected in mammals showing similar metabolism of meloxicam (Busch et al 1998; Aberg et al 2009). The metabolites of meloxicam both M1 and M2 were reported to be pharmacologically inactive (Davies and Skjodt 1999).…”