Anti-inflammatory and pharmacokinetic properties of sudoxicam N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

Wiseman, Edward H.; Chiaini, Josephine

doi:10.1016/0006-2952(72)90383-8

Cited by 33 publications

(6 citation statements)

References 12 publications

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“…The fragment ion at m/z 253 (empirical formula of C 10 H 9 O 4 N 2 S from exact mass data) is as described above for sudoxicam dihydrodiol and acylthiourea metabolites S2 and S3, respectively, and is consistent with modification on the 5-methylthiazole portion of the molecule. The unique fragment ion at m/z 200 is proposed as 3 and the fragment at m/z 198 is analogous to the fragment ion at m/z 142 for sudoxicam metabolite S3; the additional 56 mass units are due to the acetonyl moiety. It is proposed that M7 arises from a GSH mediated reduction of an imine intermediate derived from the thiazole ring opening in meloxicam (see Figure 8).…”

Section: Resultsmentioning

confidence: 99%

“…While the 4-hydroxy-2-methyl-2 H -1,2-arylthiazine-3-carboxamide 1,1-dioxide scaffold has been extensively exploited toward the discovery of new anti-inflammatory drugs, cases of failure also exist. Sudoxicam (4-hydroxy-2-methyl- N -(2-thiazolyl)-2 H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide, Figure ) was the first enol-carboxamide reported to have efficacy in various animal models of inflammation , . While the compound demonstrated anti-inflammatory action in extensive clinical trials, its clinical development was discontinued due to incidences of severe hepatotoxicity .…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Metabolism and Covalent Binding of Enol-Carboxamide Derivatives and Anti-Inflammatory Agents Sudoxicam and Meloxicam: Insights into the Hepatotoxicity of Sudoxicam

Obach

Kalgutkar

Ryder

et al. 2008

Chem. Res. Toxicol.

100

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Sudoxicam and meloxicam are nonsteroidal anti-inflammatory drugs (NSAIDs) from the enol-carboxamide class. While the only structural difference between the two NSAIDs is the presence of a methyl group on the C5-position of the 2-carboxamidothiazole motif in meloxicam, a marked difference in their toxicological profile in humans has been discerned. In clinical trials, sudoxicam was associated with several cases of severe hepatotoxicity that led to its discontinuation, while meloxicam has been in the market for over a decade and is devoid of hepatotoxicity. In an attempt to understand the biochemical basis for the differences in safety profile, an in vitro investigation of the metabolic pathways and covalent binding of the two NSAIDs was conducted in NADPH-supplemented human liver microsomes. Both compounds demonstrated NADPH-dependent covalent binding to human liver microsomes; however, the extent of binding of [(14)C]-meloxicam was approximately 2-fold greater than that of [(14)C]-sudoxicam. While inclusion of glutathione (GSH) in microsomal incubations resulted in a decrease in covalent binding for both NSAIDs, the reduction in binding was more pronounced for meloxicam. Metabolite identification studies on [(14)C]-sudoxicam in NADPH-supplemented human liver microsomes indicated that the primary route of metabolism involved a P450-mediated thiazole ring scission to the corresponding acylthiourea metabolite (S3), a well-established pro-toxin. The mechanism of formation of S3 presumably proceeds via (a) epoxidation of the C4-C5-thiazole ring double bond, (b) epoxide hydrolysis to the corresponding thiazole-4,5-dihydrodiol derivative, which was observed as a stable metabolite (S2), (c) ring opening of the thiazole-4,5-dihydrodiol to an 2-oxoethylidene thiourea intermediate, and (d) hydrolysis of the imine bond within this intermediate to yield S3. In the case of meloxicam, the corresponding acylthiourea metabolite M3 was also observed, but to a lesser extent; the main route of meloxicam metabolism involved hydroxylation of the 5'-methyl group, a finding that is consistent with the known metabolic fate of this NSAID. Inclusion of GSH led to a decrease in the formation of M3 with the concomitant formation of an unusual two-electron reduction product (metabolite M7). The formation of M7 is proposed to arise via reduction of the imine bond in 2-oxopropylidene thiourea, an intermediate in the thiazole ring scission pathway in meloxicam. In conclusion, the results of our analysis suggest that if the covalent binding of the two NSAIDs is important to the overall hepatotoxicity risk, the differences in metabolism (differential preponderance of formation of the acylthiourea relative to total metabolism), differential effects of GSH on covalent binding, and finally differences in daily doses of the two NSAIDs may serve as a plausible explanation for the marked differences in toxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Metabolism and Covalent Binding of Enol-Carboxamide Derivatives and Anti-Inflammatory Agents Sudoxicam and Meloxicam: Insights into the Hepatotoxicity of Sudoxicam

Obach

Kalgutkar

Ryder

et al. 2008

Chem. Res. Toxicol.

100

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“…The values of the covalent binding (CVB) of marketed drugs were obtained from literature references (Bergström et al, 2011;Inoue et al, 2009;Nakayama et al, 2009;Obach et al, 2008;Usui et al, 2009). The values of human oral clearance (CL/F) and maximum dose (mg/day) of 57 drugs were collected from literature references, drug labels, and the drug approval documents from FDA and EMA (Barbhaiya et al, 1996;Boik and Newman, 2008;Durand et al, 1992;Gasser et al, 1987;Kerremans et al, 1982;Li et al, 2012;Mather et al, 1981;Ward and Smith, 2004;Wiseman and Chiaini, 1972). When different values were obtained for one drug, the mean was used for further calculation.…”

Section: Data Collectionmentioning

confidence: 99%

Novel risk assessment of reactive metabolites from discovery to clinical stage

2019

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This study was aimed to predict drug-induced liver injury caused by reactive metabolites. Reactive metabolites covalently bind to proteins and could result in severe outcomes in patients. However, the relation between the extent of covalent binding and clinical hepatotoxicity is still unclear. From a perspective of body burden (human in vivo exposure to reactive metabolites), we developed a risk assessment method in which reactive metabolite burden (RM burden), an index that could reflect the body burden associated with reactive metabolite exposure, is calculated using the extent of covalent binding, clinical dose, and human in vivo clearance. The relationship between RM burden and hepatotoxicity in humans was then investigated. The results indicated that this RM burden assessment exhibited good predictability for sensitivity and specificity, and drugs with over 10 mg/day RM burden have high-risk for hepatotoxicity. Furthermore, a quantitative trapping assay using radiolabeled trapping agents ([ 35 S] cysteine and [ 14 C]KCN) was also developed, to detect reactive metabolite formation in the early drug discovery stage. RM burden calculated using this assay showed as good predictability as RM burden calculated using conventional time-and cost-consuming covalent binding assays. These results indicated that the combination of RM burden and our trapping assay would be a good risk assessment method for reactive metabolites from the drug discovery stage.

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“…Many new molecules have recently been proposed to be well tolerated AI compounds and are now in different stages of development [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Investigation of 1,3,4,9-tetrahydro-1-propylpyrano [3, 4-b] indole-1-acetic acid (prodolic acid), a new non-steroidal anti-inflammatory agent, in rats1)

Martel¹,

Klicius²,

Herr³

1974

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Prodolic acid (1,3,4,9-Tetrahydro-l-propylpyrano[3, 4-b] indole-l-aeetic acid) showed anti-inflammatory, analgesic and antipyretic properties in several experimental models in rats. In chronic types of inflammation such as the adjuvant arthritis and the cotton pellet granuloma tests, prodolic acid was up to 17 times more potent than aspirin and approximately equipotent to phenylbutazone. In acute tests such as the carrageenin, the antipyretic and the analgesic tests the potency of prodolie acid was comparable to that of aspirin. The increased potency of prodolic acid in adjuvant arthritic rats may be taken as an indication that this new compound will be particularly effective in the treatment of rheumatoid arthritis and other arthritic conditions of man. The acute toxicity of prodolic acid was 3 times less than that of phenylbutazone. Prodolic acid produced very little gastrointestinal irritation in the highest tolerated doses, while aspirin and phenylbutazone were irritant. It is concluded that prodolic acid is a promising new anti-inflammatory agent particularly potent in chronic inflammation with low systemic and low gastrointestinal toxicity.

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Anti-inflammatory and pharmacokinetic properties of sudoxicam N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

Cited by 33 publications

References 12 publications

In Vitro Metabolism and Covalent Binding of Enol-Carboxamide Derivatives and Anti-Inflammatory Agents Sudoxicam and Meloxicam: Insights into the Hepatotoxicity of Sudoxicam

In Vitro Metabolism and Covalent Binding of Enol-Carboxamide Derivatives and Anti-Inflammatory Agents Sudoxicam and Meloxicam: Insights into the Hepatotoxicity of Sudoxicam

Novel risk assessment of reactive metabolites from discovery to clinical stage

Investigation of 1,3,4,9-tetrahydro-1-propylpyrano [3, 4-b] indole-1-acetic acid (prodolic acid), a new non-steroidal anti-inflammatory agent, in rats1)

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