Sudoxicam
(Synonyms: 舒多昔康) 目录号 : GC64940
Sudoxicam 是一种可逆的口服活性的 COX 拮抗剂，是烯醇-羧酰胺类的非甾体抗炎药 (NSAID)。Sudoxicam 具有有效的抗炎，抗浮肿和退热作用。
Cas No.:34042-85-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Sudoxicam is a reversible and orally active COX antagonist and a non-steroidal anti-inflammatory drug (NSAID) from the enol-carboxamide class. Sudoxicam has potent anti-inflammatory, anti-edema and antipyretic activity[1][2][3].
Sudoxicam demonstrates NADPH-dependent covalent binding to human liver microsomes. With addition of glutathione (GSH) in microsomal incubations, about half of the covalent incorporation of Sudoxicam is blocked by addition of GSH[1].Metabolite identification studies on [14C]-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[1].In vitro, Sudoxicam underwent the oxidative thiazole-open biotransformation, resulting in the formation of an acylthiourea and the subsequent hydroxylated metabolite[3].
Sudoxicam (1-10 mg/kg; oral administration; daily; for 7 days; rats) treatment effective reduces plasma inflammation units, reduces the swelling of inflamed hind-paws and restores toward normal the daily gain in body weight[2].In the intact rat, Sudoxicam significantly inhibited edema formation at doses as low as 0.1 mg/kg, p.o[2].Sudoxicam inhibits the erythema caused by ultraviolet irradiation in the guinea pig. Sudoxicam (3.3 mg/kg, i.p.) is capable of counteracting the pyrexia induced by the intraperitoneal injection of typhoid/paratyphoid vaccine in rats, maintaining body temperature about that of uninjected control rats[2]. The plasma half-life of Sudoxicam ranged between 8 hours (monkey), 13 hours (rat), and 60 hours (dog)[2].
[1]. Obach RS, et al. In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam. Chem Res Toxicol. 2008 Sep;21(9):1890-9.
[2]. Wiseman EH, et al. Anti-inflammatory and pharmacokinetic properties of sudoxicam N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide. Biochem Pharmacol. 1972 Sep 1;21(17):2323-34.
[3]. Zhi-Yi Zhang. Sudoxicam. Handbook of Metabolic Pathways of Xenobiotics. September 2014.
| Cas No. | 34042-85-8 | SDF | Download SDF |
| 别名 | 舒多昔康 | ||
| 分子式 | C13H11N3O4S2 | 分子量 | 337.37 |
| 溶解度 | DMSO : 83.33 mg/mL (247.00 mM; ultrasonic and warming and heat to 80°C) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9641 mL | 14.8205 mL | 29.641 mL |
| 5 mM | 0.5928 mL | 2.9641 mL | 5.9282 mL |
| 10 mM | 0.2964 mL | 1.4821 mL | 2.9641 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Dual mechanisms suppress meloxicam bioactivation relative to Sudoxicam
Toxicology 2020 Jul;440:152478.PMID:32437779DOI:10.1016/j.tox.2020.152478.
Thiazoles are biologically active aromatic heterocyclic rings occurring frequently in natural products and drugs. These molecules undergo typically harmless elimination; however, a hepatotoxic response can occur due to multistep bioactivation of the thiazole to generate a reactive thioamide. A basis for those differences in outcomes remains unknown. A textbook example is the high hepatotoxicity observed for Sudoxicam in contrast to the relative safe use and marketability of meloxicam, which differs in structure from Sudoxicam by the addition of a single methyl group. Both drugs undergo bioactivation, but meloxicam exhibits an additional detoxification pathway due to hydroxylation of the methyl group. We hypothesized that thiazole bioactivation efficiency is similar between Sudoxicam and meloxicam due to the methyl group being a weak electron donator, and thus, the relevance of bioactivation depends on the competing detoxification pathway. For a rapid analysis, we modeled epoxidation of Sudoxicam derivatives to investigate the impact of substituents on thiazole bioactivation. As expected, electron donating groups increased the likelihood for epoxidation with a minimal effect for the methyl group, but model predictions did not extrapolate well among all types of substituents. Through analytical methods, we measured steady-state kinetics for metabolic bioactivation of Sudoxicam and meloxicam by human liver microsomes. Sudoxicam bioactivation was 6-fold more efficient than that for meloxicam, yet meloxicam showed a 6-fold higher efficiency of detoxification than bioactivation. Overall, Sudoxicam bioactivation was 15-fold more likely than meloxicam considering all metabolic clearance pathways. Kinetic differences likely arise from different enzymes catalyzing respective metabolic pathways based on phenotyping studies. Rather than simply providing an alternative detoxification pathway, the meloxicam methyl group suppressed the bioactivation reaction. These findings indicate the impact of thiazole substituents on bioactivation is more complex than previously thought and likely contributes to the unpredictability of their toxic potential.
Meloxicam methyl group determines enzyme specificity for thiazole bioactivation compared to Sudoxicam
Toxicol Lett 2021 Mar 1;338:10-20.PMID:33253783DOI:10.1016/j.toxlet.2020.11.015.
Meloxicam is a thiazole-containing NSAID that was approved for marketing with favorable clinical outcomes despite being structurally similar to the hepatotoxic Sudoxicam. Introduction of a single methyl group on the thiazole results in an overall lower toxic risk, yet the group's impact on P450 isozyme bioactivation is unclear. Through analytical methods, we used inhibitor phenotyping and recombinant P450s to identify contributing P450s, and then measured steady-state kinetics for bioactivation of Sudoxicam and meloxicam by the recombinant P450s to determine relative efficiencies. Experiments showed that CYP2C8, 2C19, and 3A4 catalyze Sudoxicam bioactivation, and CYP1A2 catalyzes meloxicam bioactivation, indicating that the methyl group not only impacts enzyme affinity for the drugs, but also alters which isozymes catalyze the metabolic pathways. Scaling of relative P450 efficiencies based on average liver concentration revealed that CYP2C8 dominates the Sudoxicam bioactivation pathway and CYP2C9 dominates meloxicam detoxification. Dominant P450s were applied for an informatics assessment of electronic health records to identify potential correlations between meloxicam drug-drug interactions and drug-induced liver injury. Overall, our findings provide a cautionary tale on assumed impacts of even simple structural modifications on drug bioactivation while also revealing specific targets for clinical investigations of predictive factors that determine meloxicam-induced idiosyncratic liver injury.
Metabolism of Sudoxicam by the rat, dog, and monkey
Drug Metab Dispos 1977 Jan-Feb;5(1):75-81.PMID:13979doi
Sudoxicam, N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1, 1-dioxide, was prepared in radiolabeled form and administered to rats, dogs, and monkeys. Urine contained approximately 60, 25, and 49% of the label given to rats, dogs, and monkeys, respectively; the remainder was cleared via feces. In addition to some unchanged drug, urine from all species examined contained two major metabolites. These were identified from their mass spectra as the thiohydantoic acid and thiourea resulting from scission of the thiazole ring 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
Chem Res Toxicol 2008 Sep;21(9):1890-9.PMID:18707140DOI:10.1021/tx800185b.
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.
Interaction of Sudoxicam and aspirin in animals and man
Clin Pharmacol Ther 1975 Oct;18(4):441-8.PMID:809225DOI:10.1002/cpt1975184441.
In rats, both the plasma concentrations and the anti-inflammatory activity of Sudoxicam are depressed by concurrent administration of aspirin, being similar to that reported for other nonsteroidal agents, whereas, in man and monkey, plasma concentrations of Sudoxicam are not affected by concurrent administration of aspirin. In this respect Sudoxicam differs from such other nonsteroidal anti-inflammatory agents as indomethacin and naproxen.