Rabeprazole Sulfide
(Synonyms: 2-[[[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基]硫代]-1H-苯并咪唑) 目录号 : GC39429
An active metabolite of rabeprazole
Cas No.:117977-21-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Rabeprazole sulfide is an active metabolite of the proton pump inhibitor rabeprazole .1 It inhibits the motility of H. pylori (IC50 = 0.25 ?g/ml).2 Rabeprazole sulfide is cytotoxic to HepG2 liver and PANC-1 pancreatic cancer cells (IC50s = 0.08 and 0.17 ?M, respectively).3 It is also a potential impurity in commercial preparations of rabeprazole and an acid and neutral hydrolytic degradation product of rabeprazole.4,3
1.Cao, N., Liu, L., Hao, Y.-B., et al.Simultaneous determination of rabeprazole enantiomers and their four metabolites after intravenous administration in beagle dogs by a stereoselective HPLC-MS/MS method and its application in pharmacokinetic studiesAnal. Methods81405(2016) 2.Tsutsui, N., Taneike, I., Ohara, T., et al.A novel action of the proton pump inhibitor rabeprazole and its thioether derivative against the motility of Helicobacter pyloriAntimicrob. Agents Chemother.44(11)3069-3073(2000) 3.Bhandi, M.M., Borkar, R.M., Shankar, G., et al.Identification and characterization of stressed degradation products of rabeprazole using LC-ESI/MS/MS and 1H-NMR experiments: In vitro toxicity evaluation of major degradation productsRSC Adv.610719(2016) 4.Reddy, G.M., Bhaskar, B.V., Reddy, P.P., et al.Identification and characterization of potential impurities of rabeprazole sodiumJ. Pharm. Biomed. Anal.43(4)1262-1269(2007)
| Cas No. | 117977-21-6 | SDF | |
| 别名 | 2-[[[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基]硫代]-1H-苯并咪唑 | ||
| Canonical SMILES | CC1=C(OCCCOC)C=CN=C1CSC2=NC3=CC=CC=C3N2 | ||
| 分子式 | C18H21N3O2S | 分子量 | 343.44 |
| 溶解度 | DMSO : 100 mg/mL (291.17 mM; Need ultrasonic) | 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 | 2.9117 mL | 14.5586 mL | 29.1172 mL |
| 5 mM | 0.5823 mL | 2.9117 mL | 5.8234 mL |
| 10 mM | 0.2912 mL | 1.4559 mL | 2.9117 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。
Pharmacokinetic evaluation of differential drug release formulations of Rabeprazole in dogs
Drug Dev Ind Pharm 2019 Sep;45(9):1459-1467.PMID:31216902DOI:10.1080/03639045.2019.1628249.
Objectives: To develop novel dual release prototype capsule formulations of Rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex®) in Beagle dogs. Methods: The dual release prototype formulations of Rabeprazole were developed by preparing optimized mini-tablets core which was subsequently coated with barrier/enteric coating using standard excipients. Both novel prototype formulations were subjected for in vitro release and assay by HPLC-UV to assess long term stability. Single dose pharmacokinetic study used a single sequence three treatments crossover design. In Periods 1 and 2, four dogs received oral 20 mg dose of two prototype formulations. In Period 3, all dogs received a 20 mg oral dose of Aciphex® reference product. There was a 1-week washout time between two successive periods. A quantitative analysis of Rabeprazole/sulfide metabolite in plasma samples was performed using a validated LC-MS/MS assay and PK parameters were estimated by non-compartmental analysis. Results: The stability of the prototype formulations was confirmed over a period of 24 months with an acceptable assay and dissolution data. One of the novel prototype formulations showed 70% oral bioavailability relative to the reference product. Despite a 30% reduced bioavailability, this showed 1 h delay in peak concentration, longer plasma residence time of Rabeprazole (up to 12 h) and longer apparent elimination half-life. Conclusions: The use of a canine model has enabled the selection of a novel dual-release prototype formulation of Rabeprazole for further clinical development.
Stereoselective metabolism of rabeprazole-thioether to Rabeprazole by human liver microsomes
Eur J Clin Pharmacol 2006 Feb;62(2):113-7.PMID:16389533DOI:10.1007/s00228-005-0077-8.
Objective: Rabeprazole is metabolized mainly non-enzymatically to rabeprazole-thioether. This in vitro study was designed to clarify the stereoselective oxidation mechanism and to identify the enzyme(s) involved in the metabolic breakdown of rabeprazole-thioether to Rabeprazole. Methods: Rabeprazole-thioether was incubated with human liver microsomes and several recombinant cytochrome P450 (CYP) enzymes (CYPs 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4). High-performance liquid chromatography was used for identification and quantification of each Rabeprazole enantiomer. Results: The K(m ) and V(max ) values for the formation of (R)-rabeprazole from rabeprazole-thioether in human liver microsomes were 6.6 microM and 92 pmol/min/mg protein, respectively, whereas those for the formation of (S)-rabeprazole were 5.1 microM and 21 pmol/min/mg protein, respectively. CYP3A4 was found to be the major enzyme responsible for(R)- and (S)-rabeprazole formation from rabeprazole-thioether. The intrinsic clearance (V(max ) /K(m )) for the oxidation by CYP3A4 of (R)-rabeprazole was 3.5-fold higher than that for the (S)-enantiomer (81 nl/min/pmol of P450 vs. 23 nl/min/pmol of P450). On the other hand, CYP2C19 and CYP2D6 were the main enzymes catalyzing the formation of desmethylrabeprazole-thioether from rabeprazole-thioether. The mean K(m ) and V(max ) values of desmethylrabeprazole-thioether formation for CYP2C19 were 5.1 microM and 600 pmol/min/nmol of P450, respectively, whereas those for CYP2D6 were 15.1 microM and 736 pmol/min/nmol of P450, respectively. Discussion: Rabeprazole is reduced mainly non-enzymatically to rabeprazole-thioether, which is further stereoselectively re-oxidized by CYP3A4 mainly to (R)-rabeprazole. The difference in the enantioselective disposition of Rabeprazole is determined by stereoselectivity in CYP3A4-mediated metabolic conversion from rabeprazole-thioether to Rabeprazole.
Stereoselective disposition of proton pump inhibitors
Clin Drug Investig 2008;28(5):263-79.PMID:18407713DOI:10.2165/00044011-200828050-00001.
It is estimated that about half of all therapeutic agents are chiral, but most of these drugs are administered in the form of the racemic mixture, i.e. a 50/50 mixture of its enantiomers. However, chirality is one of the main features of biology, and many of the processes essential for life are stereoselective, implying that two enantiomers may work differently from each other in a physiological environment. Thus, receptors or metabolizing enzymes would recognize one of the ligand enantiomers in favour of the other. With one exception, all presently marketed proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole and rabeprazole--used for the treatment of gastric acid-related diseases are racemic mixtures. The exception is esomeprazole, the S-enantiomer of omeprazole, which is the only PPI developed as a single enantiomer drug. The development of esomeprazole (an alkaline salt thereof, e.g. magnesium or sodium) was based on unique metabolic properties that clearly differentiated esomeprazole from omeprazole, the racemate. At comparable doses, these properties led to several clinical advantages, for example higher bioavailability in the majority of patients, i.e. the extensive metabolizers (EMs; 97% in Caucasian and 80-85% in Asian populations), lower exposure in poor metabolizers (PMs; 3% in Caucasian and 15-20% in Asian populations) and lower interindividual variation. For the other, i.e. racemic, PPIs there are some data available on the characteristics of the individual enantiomers, and we have therefore undertaken to analyse the current literature with the purpose of evaluating the potential benefits of developing single enantiomer drugs from lansoprazole, pantoprazole and Rabeprazole. For lansoprazole, the plasma concentrations of the S-enantiomer are lower than those of the R-enantiomer in both EMs and PMs, and, consequently, the variability in the population or between EMs and PMs is not likely to decrease with either of the lansoprazole enantiomers. Furthermore, plasma protein binding differs between the two lansoprazole enantiomers, in that the amount of the free S-enantiomer is two-fold higher than that of the R-enantiomer. This will counteract the difference seen in total plasma concentrations of the enantiomers. Also, studies using expressed human cytochrome P450 isoenzymes show that the metabolism of one enantiomer is significantly affected by the presence of the other, which is likely to result in different pharmacokinetics when administering a single enantiomer. For pantoprazole, there is a negligible difference in plasma concentrations between the two enantiomers in EMs, while the difference is substantial in PMs. The difference in AUC between PMs and EMs would decrease to some extent, but in the majority of the population the variability and efficacy would not be altered with a single enantiomer of pantoprazole. The metabolism of the enantiomers of Rabeprazole displays stereoselectivity comparable to that of lansoprazole, i.e. the exposure of the R-enantiomer is higher than that of the S-enantiomer in EMs as well as in PMs, which, by analogy to lansoprazole, makes them less suitable for development of a single enantiomer drug. Furthermore, the chiral stability of the Rabeprazole enantiomers may be an issue because of significant degradation of Rabeprazole to its sulfide analogue, which is subject to non-stereoselective metabolic regeneration of a mixture of the two enantiomers. In conclusion, in contrast to esomeprazole, the S-enantiomer of omeprazole, minimal if any clinical advantages would be expected in developing any of the enantiomers of lansoprazole, pantoprazole, or Rabeprazole as compared with their racemates.
Simultaneous determination of Rabeprazole and its two active metabolites in human urine by liquid chromatography with tandem mass spectrometry and its application in a urinary excretion study
J Sep Sci 2014 Aug;37(15):1951-6.PMID:24798930DOI:10.1002/jssc.201400162.
A simple and rapid liquid chromatography with tandem mass spectrometry method has been developed and validated for the determination of Rabeprazole and its two active metabolites, Rabeprazole thioether and desmethyl Rabeprazole thioether, in human urine using donepezil as the internal standard. The sample preparation procedure involved a simple dilution of urine sample with methanol (1:3, v/v). The chromatographic separation was achieved on a Hedera ODS-2 C18 column using a mixture of methanol/10 mmol/L ammonium acetate solution (containing 0.05% formic acid; 55:45, v/v) as the mobile phase. The method was validated over the concentration ranges of 0.15-100 ng/mL for Rabeprazole, 0.30-400 ng/mL for Rabeprazole thioether, and 0.05-100 ng/mL for desmethyl Rabeprazole thioether. The established method was highly sensitive with a lower limit of quantification of 0.15 ng/mL for Rabeprazole, 0.30 ng/mL for Rabeprazole thioether, and 0.05 ng/mL for desmethyl Rabeprazole thioether. The intra- and interbatch precision was <4.5% for the low, medium, and high quality control samples of all the analytes. The recovery of the analytes was in the range 95.4-99.0%. The method was successfully applied to a urinary excretion profiles after intravenous infusion administration of 20 mg Rabeprazole sodium in healthy volunteers.
Pharmacokinetics and tolerability of Rabeprazole in children 1 to 11 years old with gastroesophageal reflux disease
J Pediatr Gastroenterol Nutr 2011 Jun;52(6):691-701.PMID:21478756DOI:10.1097/MPG.0b013e318207834d.
Background: The pharmacokinetics of Rabeprazole after a single oral dose and once-daily administration for 5 consecutive days was characterized in children 1 to 11 years old with gastroesophageal reflux disease (GERD). Patients and methods: The initial 8 patients received Rabeprazole sodium (hereafter referred to as Rabeprazole) 0.14 mg/kg (part 1); the next 20 patients were randomized to receive 0.5 or 1 mg/kg (part 2) to target concentrations in plasma expected to be safe and effective. Pharmacokinetic parameters of Rabeprazole and the thioether metabolite were calculated using noncompartmental methods. Subjective evaluations of GERD severity, Rabeprazole short-term effectiveness, palatability, and safety were also characterized. Results: Rabeprazole concentrations increased in a dose-dependent manner. Little or no accumulation was observed after repeated administration. The results suggest that formation of the thioether is an important metabolic pathway in young patients, which is consistent with adults. Plasma area under the concentration-time curve values of Rabeprazole and the metabolite were poorly correlated with individual age and body weight. Furthermore, oral Rabeprazole clearance values (not adjusted for weight) were similar to historical adult data. However, weight-adjusted values were higher for the pediatric patients, and approximately 2 to 3 times the milligram per kilogram dose of Rabeprazole in these children was necessary to achieve comparable concentrations in adults. Subjective evaluations demonstrated an improvement of GERD symptoms in most patients after Rabeprazole treatment. Conclusions: Palatability of the formulation was reported to be good or excellent. Rabeprazole was well tolerated, with no notable differences in safety among the dose groups.