Oxicams: Metabolic Disposition in Man and Animals

Woolf, Thomas F.; Radulovic, Louis L.

doi:10.3109/03602538909029942

Cited by 38 publications

(19 citation statements)

References 29 publications

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“…a carboxybenzothiazine and a benzothiazine metabolite of piroxicam have been detected in rat, dog, monkey and man. [1] Another metabolite that is considered typical for oxicams is the oxoacetic acid metabolite. [1,7] However, in this study none of these metabolites was detected.…”

Section: Other Phase I Metabolitesmentioning

confidence: 99%

“…[6] Oglucuronides have been detected in bile from humans and rats after oxidation of the thienothiazine moity of tenoxicam resulting in 7-or 8-O-glucuronyltenoxicam and in human urine after oxidation of the benzothiazine group in piroxicam yielding 5 -O-glucuronylpiroxicam. [1] In our study, the horse urine was diluted and injected without further sample preparation into the triple quadrupole mass spectrometer in order to search for phase II metabolites. MS/MS scans of m/z for possible conjugates were applied and in Fig.…”

Section: Hydroxymeloxicam Glucuronidementioning

confidence: 99%

“…1). 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.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2009

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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.

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Section: Other Phase I Metabolitesmentioning

confidence: 99%

Section: Hydroxymeloxicam Glucuronidementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2009

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“…Recently, this open-ring sulfonamide along with N-methylsaccharin and saccharin were identified in urine of rats, dogs and monkeys administered [14C]-isoxicam with the label in the N-methyl moiety (Scheme 2) (11,12). Although present in relatively minor amounts, these metabolites nevertheless show the existence of a 'saccharin pathway' in isoxicam's metabolic disposition in rat, dog and monkey.…”

Section: Introductionmentioning

confidence: 99%

Metabolic disposition of the non-steroidal anti-inflammatory agent isoxicam in man

Woolf¹,

Black²,

Sedman³

et al. 1992

European Journal of Drug Metabolism and Pharmacokinetics

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The metabolic fate of isoxicam, a long half-life non-steroidal anti-inflammatory agent, in human subjects was investigated using isoxicam labelled with 14C in the N-methyl position. Three healthy male subjects were each administered a single oral 200 mg dose (90.7 microCi) with plasma and urine collected. Total plasma radioactivity peaked between 8 and 24 h postdose with mean 14C plasma radioactivity half-life of 36.1 h. Low levels of plasma radioactivity precluded plasma metabolic profiling. In urine, 37% of the administered radioactivity was recovered through 168 h. Metabolic profiling of urine confirmed the major oxidative excretion product as the hydroxymethylisoxazole metabolite. Identified and confirmed as minor urinary metabolites were radiolabelled open-ring sulfonamide and N-methylsaccharin. Non-labelled saccharin formed by oxidative loss of the 14C N-methyl group from N-methylsaccharin, was also observed. The role of this 'saccharin pathway' in the overall human disposition of isoxicam remains to be elucidated.

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“…Like tenoxicam, piroxicam is metabolized extensively and only a minor fraction of the dose (Յ10%) is recovered unchanged (Brogden et al, 1984;Richardson et al, 1987;Woolf and Radulovic, 1989;Olkkola et al, 1994). Although various metabolites have been identified in human excreta, 5Ј-hydroxy piroxicam is the major metabolite and accounts for about 60% of the dose (f m ϳ0.6) (Richardson et al, 1987).…”

Section: Rodriguesmentioning

confidence: 99%

IMPACT OFCYP2C9GENOTYPE ON PHARMACOKINETICS: ARE ALL CYCLOOXYGENASE INHIBITORS THE SAME?: TABLE 1

Rodrigues¹

2005

Drug Metab Dispos

103

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ABSTRACT:The market withdrawals of rofecoxib (Vioxx) and valdecoxib (Bextra) have focused considerable attention on the side effect profiles of cyclooxygenase (COX) inhibitors. As a result, attempts will be made to identify risk factors in the hope that physicians might be able to ensure patient safety. At first glance, CYP2C9 genotype might be considered a risk factor because many COX inhibitors are CYP2C9 substrates in vitro. This observation has led some to hypothesize that a reduction in clearance, in subjects expressing variant forms of the enzyme (e.g., CYP2C9*1/*3 or CYP2C9*3/*3 genotype), will lead to increased exposure and a greater risk of cardiovascular or gastrointestinal side effects. For any drug, however, one has to consider all clearance pathways. Therefore, a number of COX inhibitors were surveyed and it was determined that CYP2C9 plays a relatively minor role in the overall clearance (<20% of the dose) of sulindac, naproxen, ketoprofen, diclofenac, rofecoxib, and etoricoxib. CYP2C9 genotype would have no clinically meaningful impact on the pharmacokinetics of these drugs. In contrast, CYP2C9 genotype is expected to impact the clearance of ibuprofen, indomethacin, flurbiprofen, celecoxib, valdecoxib, lornoxicam, tenoxicam, meloxicam, and piroxicam. However, even when CYP2C9 is a major determinant of clearance, it is necessary to consider CYP2C8 genotype (e.g., ibuprofen) and, possibly, CYP3A4 activity (e.g., celecoxib, valdecoxib, and meloxicam) also.Events surrounding the market withdrawal of rofecoxib (Vioxx), a potent and selective COX-2 inhibitor, have raised concerns about the safety of other COX-2 selective inhibitors such as etoricoxib (Arcoxia), celecoxib (Celebrex), lumiracoxib (Prexige), and valdecoxib (Bextra) (Mukherjee et al., 2002;Bing, 2003;Couzin, 2004;Davies and Jamali, 2004;Fitzgerald, 2004;Kim and Reicin, 2004;Ray et al., 2004;Scheen, 2004;Bannwarth, 2005;Berenbaum, 2005). Such concerns finally resulted in the withdrawal of valdecoxib about seven months after the withdrawal of rofecoxib (Lenzer, 2005;Young, 2005). Nonselective COX inhibitors (NSAIDs) like naproxen, diclofenac, and ibuprofen have also come under scrutiny from regulators, physicians, and patient safety advocacy groups (McGettigan and Henry, 2000;Meagher, 2003).At the present time, it is thought that the CV and GI side effects of COX inhibitors are related to their mechanism of action. This involves the inhibition of COX, a hemeprotein that exists in two forms (COX-1 and COX-2). COX-1 is expressed constitutively in most tissues, whereas the expression of COX-2 can be induced by growth factors, cytokines, and vasoactive peptides such as endothelin. In response to cell damage, therefore, COX-2 is inducible by proinflammatory mediators and plays a role in the generation of prostaglandin E 2 , a major mediator of inflammatory response. On the other hand, the products of COX-1 are cytoprotective in GI epithelium, and selective inhibition of COX-2 is anticipated to reduce inflammation, and modulate pain, without the GI...

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Oxicams: Metabolic Disposition in Man and Animals

Cited by 38 publications

References 29 publications

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

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

Metabolic disposition of the non-steroidal anti-inflammatory agent isoxicam in man

IMPACT OFCYP2C9GENOTYPE ON PHARMACOKINETICS: ARE ALL CYCLOOXYGENASE INHIBITORS THE SAME?: TABLE 1

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