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Kim J, Kang C, Yoo JW, Yoon IS, Jung Y. Colon-Targeted β 3-Adrenoceptor Agonist Mirabegron Enhances Anticolitic Potency of the Drug via Potentiating the Nrf2-HO-1 Pathway. Mol Pharm 2025; 22:2431-2445. [PMID: 40241685 DOI: 10.1021/acs.molpharmaceut.4c01041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
The selective agonist of β3-adrenergic receptor mirabegron (MBG), clinically used to treat overactive bladders, exerts beneficial effects in animal models of colitis. Here, we aimed to enhance the therapeutic activity and safety of MBG as an anticolitic drug by implementing colon-targeted drug delivery using a prodrug approach. MBG was azo-linked with salicylic acid (SA) to yield SA-conjugated MBG (MAS), which was conjugated with aspartic acid (Asp) and glutamic acid (Glu) to yield more hydrophilic derivatives: Asp-conjugated MAS (MAS-Asp) and Glu-conjugated MAS (MAS-Glu). MBG derivatives reduced the distribution coefficient and cell permeability of MBG, which were greater with the amino acid-conjugated MAS than with MAS. MBG derivatives were cleaved to release MBG in the cecal contents. Upon oral gavage, compared with MBG, MBG derivatives delivered greater amounts of MBG to the cecum while limiting the systemic absorption of MBG, and the amino acid-conjugated MAS exhibited a greater performance than MAS. In a rat colitis model, MBG derivatives were more effective than MBG in ameliorating colonic damage and inflammation, and the amino acid-conjugated MAS was more potent than MAS. MAS-Glu was therapeutically superior to sulfasalazine, a current drug to treat inflammatory bowel disease, against rat colitis. Moreover, MBG activated the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2)-hemeoxygenase (HO)-1 pathway in inflamed colonic tissue, and the MAS-Glu-mediated amelioration of colitis was significantly compromised by an HO-1 inhibitor. Taken together, colon-targeted delivery of MBG may enhance the anticolitic activity, reduce the risk of systemic side effects of MBG, and elicit the therapeutic effects, at least partly by activating the Nrf2-HO-1 pathway.
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Affiliation(s)
- Jaejeong Kim
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Changyu Kang
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Jin-Wook Yoo
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
| | - In-Soo Yoon
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
| | - Yunjin Jung
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
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Kang C, Kim J, Jeong Y, Yoo JW, Jung Y. Colon-Targeted Poly(ADP-ribose) Polymerase Inhibitors Synergize Therapeutic Effects of Mesalazine Against Rat Colitis Induced by 2,4-Dinitrobenzenesulfonic Acid. Pharmaceutics 2024; 16:1546. [PMID: 39771525 PMCID: PMC11728683 DOI: 10.3390/pharmaceutics16121546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/14/2024] [Accepted: 11/25/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA.
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Affiliation(s)
| | | | | | | | - Yunjin Jung
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (C.K.); (J.K.); (Y.J.); (J.-W.Y.)
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Lee H, Park S, Ju S, Kim S, Yoo JW, Yoon IS, Min DS, Jung Y. Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent. Mol Pharm 2021; 18:1730-1741. [PMID: 33661643 DOI: 10.1021/acs.molpharmaceut.0c01228] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Microbial metabolites play a critical role in mucosal homeostasis by mediating physiological communication between the host and colonic microbes, whose perturbation may lead to gut inflammation. The microbial metabolite 3-indolepropionic acid (3-IPA) is one such communication mediator with potent antioxidative and anti-inflammatory activity. To apply the metabolite for the treatment of colitis, 3-IPA was coupled with acidic amino acids to yield colon-targeted 3-IPA, 3-IPA-aspartic acid (IPA-AA) and 3-IPA-glutamic acid (IPA-GA). Both conjugates were activated to 3-IPA in the cecal contents, which occurred faster for IPA-AA. Oral gavage of IPA-AA (oral IPA-AA) delivered a millimolar concentration of IPA-AA to the cecum, liberating 3-IPA. In a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model, oral IPA-AA ameliorated rat colitis and was less effective than sulfasalazine (SSZ), a current anti-inflammatory bowel disease drug. To enhance the anticolitic activity of 3-IPA, it was azo-linked with the GPR109 agonist 5-aminonicotinic acid (5-ANA) to yield IPA-azo-ANA, expecting a mutual anticolitic action. IPA-azo-ANA (activated to 5-ANA and 2-amino-3-IPA) exhibited colon specificity in in vitro and in vivo experiments. Oral IPA-azo-ANA mitigated colonic damage and inflammation and was more effective than SSZ. These results suggest that colon-targeted 3-IPA ameliorated rat colitis and its anticolitic activity could be enhanced by codelivery of the GPR109A agonist 5-ANA.
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Affiliation(s)
- Hanju Lee
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Sohee Park
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Sanghyun Ju
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Soojin Kim
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Jin-Wook Yoo
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - In-Soo Yoon
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Do Sik Min
- College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Yunjin Jung
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
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El-Nagar MK, Abdu-Allah HH, Salem OI, Kafafy AHN, Farghaly HS. Novel N-substituted 5-aminosalicylamides as dual inhibitors of cyclooxygenase and 5-lipoxygenase enzymes: Synthesis, biological evaluation and docking study. Bioorg Chem 2018; 78:80-93. [DOI: 10.1016/j.bioorg.2018.02.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/22/2018] [Accepted: 02/22/2018] [Indexed: 10/17/2022]
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Yousefi S, Bayat S, Rahman MBA, Ibrahim Z, Abdulmalek E. Synthesis and in vitro Bioactivity Evaluation of New Galactose and Fructose Ester Derivatives of 5-Aminosalicylic Acid. Chem Biodivers 2016; 14. [PMID: 28036129 DOI: 10.1002/cbdv.201600362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 12/28/2016] [Indexed: 02/02/2023]
Abstract
Inflammatory bowel disease (IBD) is the main risk factor for developing colorectal cancer which is common in patients of all ages. 5-Aminosalicylic acid (5-ASA), structurally related to the salicylates, is highly active in the treatment of IBD with minor side effects. In this study, the synthesis of galactose and fructose esters of 5-ASA was planned to evaluate the role of glycoconjugation on the bioactivity of the parent drug. The antibacterial activity of the new compounds were evaluated against two Gram-negative and two Gram-positive species of bacteria, with a notable effect observed against Staphylococcus aureus and Escherichia coli in comparisons with the 5-ASA. Cytotoxicity testing over HT-29 and 3T3 cell lines indicated that the toxicity of the new products against normal cells was significantly reduced compared with the original drug, whereas their activity against cancerous cells was slightly decreased. The anti-inflammatory activity test in RAW264.7 macrophage cells indicated that the inhibition of nitric oxide by both of the monosaccharide conjugated derivatives was slightly improved in comparison with the non-conjugated drug.
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Affiliation(s)
- Samira Yousefi
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, UPM Serdang, Selangor, Malaysia
| | - Saadi Bayat
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, UPM Serdang, Selangor, Malaysia
| | - Mohd Basyaruddin Abdul Rahman
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, UPM Serdang, Selangor, Malaysia.,Enzyme and Microbial Technology Centre, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.,Structural and Synthetic Biology Research Center, Malaysia Genome Institute, 43600, Bangi, Selangor, Malaysia
| | - Zalikha Ibrahim
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, UPM Serdang, Selangor, Malaysia
| | - Emilia Abdulmalek
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, UPM Serdang, Selangor, Malaysia.,Enzyme and Microbial Technology Centre, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
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7
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Yousefi S, Bayat S, Rahman MBA, Ismail IS, Saki E, Leong SW, Abdulmalek E. Synthesis, bioactivity evaluation, and docking study of 5-aminosalicylic acid’s fatty acid derivatives. MONATSHEFTE FUR CHEMIE 2015. [DOI: 10.1007/s00706-015-1538-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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8
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Yousefi S, Bayat S, Abdul Rahman MB, Ismail IS, Saki E, Abdulmalek E. Synthesis and in vitro bioactivity evaluation of new glucose and xylitol ester derivatives of 5-aminosalicylic acid. RSC Adv 2015. [DOI: 10.1039/c5ra19623j] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Synthesis,in vitroanti-bacterial, anti-inflammatory and anti-cancer activity evaluations andin silicostudy of monosaccharide derivatives of mesalazine in comparison with parent drug.
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Affiliation(s)
- Samira Yousefi
- Department of Chemistry
- Faculty of Science
- Universiti Putra Malaysia
- 43400 UPM Serdang
- Malaysia
| | - Saadi Bayat
- Department of Chemistry
- Faculty of Science
- Universiti Putra Malaysia
- 43400 UPM Serdang
- Malaysia
| | | | - Intan Safinar Ismail
- Department of Chemistry
- Faculty of Science
- Universiti Putra Malaysia
- 43400 UPM Serdang
- Malaysia
| | - Elnaz Saki
- Department of Cell and Molecular Biology
- Faculty of Biotechnology and Biomolecular Sciences
- Universiti Putra Malaysia
- 43400 Serdang
- Malaysia
| | - Emilia Abdulmalek
- Department of Chemistry
- Faculty of Science
- Universiti Putra Malaysia
- 43400 UPM Serdang
- Malaysia
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Dhaneshwar S, Kusurkar M, Bodhankar S, Bihani G. Carrier-linked mutual prodrugs of biphenylacetic acid as a promising alternative to bioprecursor fenbufen: design, kinetics, and pharmacological studies. Inflammopharmacology 2013; 22:235-50. [PMID: 24178955 DOI: 10.1007/s10787-013-0194-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 10/04/2013] [Indexed: 11/29/2022]
Abstract
Novel mutual prodrugs of biphenylacetic acid were designed as a promising gastro-protective alternative to fenbufen. Biphenyacetic acid was covalently linked with two non-essential amino acids (D-phenylalanine and glycine) possessing wound healing, analgesic, and anti-inflammatory properties. The prodrugs exhibited good stability in stomach homogenates while hydrolytic release of biphenylacetic acid was observed in phosphate buffer, small intestinal homogenates, and 80% human plasma. In vivo behavior of prodrugs on oral administration to Wistar rats demonstrated 33-45% release of biphenylacetic acid in blood over a period of 24 h indicating passage of intact prodrugs to colon, colonic release of parent drug followed by its absorption through colonic mucosa into systemic circulation. Prodrugs were extensively evaluated for analgesic, anti-inflammatory, anti-arthritic, and ulcerogenic activities. Biochemical, haemetological, histopathological, and radiological studies were also performed. Conversion of bioprecusor fenbufen into mutual carrier-linked prodrugs proved to be promising alternative in terms of reduced ulcerogenic propensity, longer duration of analgesia, enhanced/prolonged anti-inflammatory activity, and superior anti-arthritic effect. These prodrugs could be developed further for chronotherapy of rheumatoid arthritis.
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Affiliation(s)
- Suneela Dhaneshwar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune, 411038, Maharashtra, India,
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10
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Karaman R. Prodrugs Design Based on Inter- and Intramolecular Chemical Processes. Chem Biol Drug Des 2013; 82:643-68. [DOI: 10.1111/cbdd.12224] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 08/13/2013] [Accepted: 08/16/2013] [Indexed: 01/29/2023]
Affiliation(s)
- Rafik Karaman
- Bioorganic Chemistry Department; Faculty of Pharmacy; Al-Quds University; P.O. Box 20002 Jerusalem Palestine
- Department of Science; University of Basilicata; Via dell'Ateneo Lucano 10 85100 Potenza Italy
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11
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Huttunen KM, Tani N, Juvonen RO, Raunio H, Rautio J. Design, synthesis, and evaluation of novel cyclic phosphates of 5-aminosalicylic acid as cytochrome p450-activated prodrugs. Mol Pharm 2012; 10:532-7. [PMID: 22937971 DOI: 10.1021/mp300330v] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Four novel cyclic phosphates of the anti-inflammatory agent 5-aminosalicylic acid (5-ASA) were designed and synthesized as cytochrome P450 (CYP)-activated prodrugs. These prodrugs can be used for targeting into gut wall, since these types of cyclic phosphates are known to be activated mainly by CYP3A forms, which are expressed not only in the liver but also in the small intestine and to a lesser extent in the colon. The present study shows that aromatic ring activating substituents, like chlorine, are definitely needed to obtain the desired enzymatic cleavage of the cyclic phosphate prodrugs of 5-ASA. However, the position of the activating substituent has also a strong impact on the chemical stability, and therefore, an appropriate balance between the rates of prodrug bioactivation and chemical stability needs to be taken into consideration in future studies on cyclic phosphate prodrugs of 5-ASA.
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Affiliation(s)
- Kristiina M Huttunen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
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Lee Y, Jung EH, Kim H, Yoon JH, Kim DD, Jung Y. Preparation and in vitro evaluation of celecoxib-amino acid conjugates as a colon specific prodrug. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2012. [DOI: 10.1007/s40005-012-0018-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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13
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Kong H, Kim H, Do H, Lee Y, Hong S, Yoon JH, Jung Y, Kim YM. Structural effects of N-aromatic acyl-amino acid conjugates on their deconjugation in the cecal contents of rats: implication in design of a colon-specific prodrug with controlled conversion rate at the target site. Biopharm Drug Dispos 2011; 32:343-54. [PMID: 21800327 DOI: 10.1002/bdd.763] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 05/31/2011] [Accepted: 06/16/2011] [Indexed: 11/06/2022]
Affiliation(s)
- Hyesik Kong
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Hyunjeong Kim
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Heejeong Do
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Yonghyun Lee
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Sungchae Hong
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Jeong-Hyun Yoon
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Yunjin Jung
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Young Mi Kim
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
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Aguzzi C, Ortega A, Bonferoni M, Sandri G, Cerezo P, Salcedo I, Sánchez R, Viseras C, Caramella C. Assessement of anti-inflammatory properties of microspheres prepared with chitosan and 5-amino salicylic acid over inflamed Caco-2 cells. Carbohydr Polym 2011. [DOI: 10.1016/j.carbpol.2011.03.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Dhaneshwar S, Tewari K, Joshi S, Godbole D, Ghosh P. Diglyceride prodrug strategy for enhancing the bioavailability of norfloxacin. Chem Phys Lipids 2011; 164:307-13. [PMID: 21477584 DOI: 10.1016/j.chemphyslip.2011.03.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2011] [Revised: 03/25/2011] [Accepted: 03/28/2011] [Indexed: 10/18/2022]
Abstract
Prodrug approach using diglyceride as a promoiety is a promising strategy to improve bioavailability of poorly absorbed drugs and the same was explored in the present work to improve oral bioavailability of norfloxacin; a second generation fluoroquinolone antibacterial. The prodrug was synthesized by standard procedures using dipalmitine as a carrier and the structure was confirmed by spectral analysis. Higher LogP indicated improved lipophilicity. The ester linkage between norfloxacin and dipalmitine would be susceptible to hydrolysis by lipases to release the parent drug and carrier in the body. In vivo kinetic studies in rats indicated 53% release of norfloxacin in plasma at the end of 8h. The prodrug exhibited improved pharmacological profile than the parent compound at equimolar dose that indirectly indicated improved bioavailability.
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Affiliation(s)
- Suneela Dhaneshwar
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, Maharashtra, India.
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Structural Analysis of 5-aminosalicyl-L-glutamic Acid, a Colon-specific Prodrug of 5-aminosalicylic Acid, for Colon-specific Deconjugation. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2010. [DOI: 10.4333/kps.2010.40.4.213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Box-Behnken experimental design in the development of pectin-compritol ATO 888 compression coated colon targeted drug delivery of mesalamine. ACTA PHARMACEUTICA 2010; 60:39-54. [PMID: 20228040 DOI: 10.2478/v10007-010-0008-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The aim of this study was to investigate the combined influence of 3 independent variables in the compression coated tablet of mesalamine for ulcerative colitis. A 3-factor, 3-level Box-Behnken design was used to derive a second order polynomial equation and construct contour plots to predict responses. The independent variables selected were: percentage of polymers (pectin and compritol ATO 888) in compression coating (X(1)), coating mass (X(2)) and coating force (X(3)). Fifteen batches were prepared and evaluated for percent of drug released in 5 h (Y(5)), time required for 50 % mesalamine to dissolve (t(50)) with rat cecal (RC) content and without rat cecal content (t(50)), percent of drug released in 24 h in the presence of rat cecal content (Y(24) with RC). Transformed values of independent and dependent variables were subjected to multiple regressions to establish a full-model second-order polynomial equation. F was calculated to confirm the omission of insignificant terms from the full-model equation. The computer optimization process and contour plots predicted the levels of independent variables X(1), X(2), and X(3) (0, 0.2 and -0.15, respectively) for colon targeting and total percent of drug released up to 24 h.
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Jung Y, Kim YM. What should be considered on design of a colon-specific prodrug? Expert Opin Drug Deliv 2010; 7:245-58. [DOI: 10.1517/17425240903490401] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Kim H, Huh J, Jeon H, Choi D, Han J, Kim Y, Jung Y. N,N'-Bis(5-aminosalicyl)-L-cystine is a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis. J Pharm Sci 2009; 98:159-68. [PMID: 18399548 DOI: 10.1002/jps.21404] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
To evaluate N,N'-bis(5-aminosalicyl)-L-cystine (5-ASA-Cys) as a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis, the pharmacokinetics and therapeutic activity were investigated after oral administration of 5-ASA-Cys and amelioration of experimental colitis was compared after rectal administration of 5-aminosalicylic acid (5-ASA) and/or cysteine. In addition, the gluthathione (GSH) level in the inflamed colonic tissue was examined after administration of cysteine or 5-ASA-Cys. Oral administration of 5-ASA-Cys delivered much greater amount of 5-ASA to the large intestine and excreted lower amount of 5-ASA via urine than that of free 5-ASA. Oral administration of 5-ASA-Cys ameliorated experimental colitis of rats induced by TNBS, which was more effective than that of sulfasalazine. Although cysteine administered rectally was not significantly effective, intracolonic treatment with both 5-ASA and cysteine showed a synergic effect in alleviating the rat colitis. Furthermore, not only 5-ASA-Cys administered orally but also cysteine administered rectally increased the glutathione level in the inflamed colonic tissue. Taken together, these results suggest that 5-ASA-Cys is a potential colon specific 5-ASA prodrug with dual therapeutic effects on experimental colitis and cysteine modulation of the glutathione level may be relevant to the dual effects of the prodrug.
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Affiliation(s)
- Heejung Kim
- Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609-735, South Korea
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Vadnerkar G, Dhaneshwar S. Design and development of latentiated strategy for delivery of mesalazine to colon. J Drug Deliv Sci Technol 2009. [DOI: 10.1016/s1773-2247(09)50067-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Lee J, Rho J, Yang Y, Kong H, Jung Y, Kim Y. Synthesis andin vitroevaluation ofN-nicotinoylglycyl-2-(5-fluorouracil-1-yl)-d,l-glycine as a colon-specific prodrug of 5-fluorouracil. J Drug Target 2008; 15:199-205. [PMID: 17454357 DOI: 10.1080/10611860701197508] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
N-Nicotinoylglycyl-2-(5-fluorouracil-1-yl)-D,L-glycine (NGFG) was synthesized as a colon-specific prodrug of 5-fluorouracil (5-FU) expecting that hydrolysis of nicotinoyl and glycyl moieties by microbial enzymes in the colon will give 2-(5-fluorouracil-1-yl)-D,L-glycine, which releases 5-FU spontaneously. To in vitro-evaluate colon targetability of NGFG, apparent partition coefficient and chemical/biochemical stability of NGFG in the contents or/and tissue of the various segments of the gastrointestinal tract were determined. Low partition coefficient and stability of NGFG in the upper intestinal condition suggested its delivery to the colon in intact form after oral administration. Incubation with rat cecal contents produced 5-FU and its metabolite about 16%. Structural modification to enhance amide hydrolysis, the rate determining step in NGFG bioactivation, is suggested.
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Affiliation(s)
- Jeoungsoo Lee
- Bioengineering Department, Clemson University, Clemson, SC 29634, USA
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23
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Oral colon targeted delivery systems for treatment of inflammatory bowel diseases: Synthesis, in vitro and in vivo assessment. Int J Pharm 2008; 358:248-55. [DOI: 10.1016/j.ijpharm.2008.04.021] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2008] [Revised: 04/07/2008] [Accepted: 04/14/2008] [Indexed: 01/26/2023]
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24
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Simplício AL, Clancy JM, Gilmer JF. Prodrugs for amines. Molecules 2008; 13:519-47. [PMID: 18463563 PMCID: PMC6245426 DOI: 10.3390/molecules13030519] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2007] [Revised: 02/25/2008] [Accepted: 02/25/2008] [Indexed: 11/21/2022] Open
Abstract
The purpose of this work is to review the published strategies for the production of prodrugs of amines. The review is divided in two main groups of approaches: those that rely on enzymatic activation and those that take advantage of physiological chemical conditions for release of the drugs. A compilation of the most important approaches is presented in the form of a table, where the main advantages and disadvantages of each strategy are also referred.
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Affiliation(s)
- Ana L. Simplício
- Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República – EAN, 2780-157 Oeiras, Portugal
- IBET, Apartado 12, 2781-901 Oeiras, Portugal
- Author to whom correspondence should be addressed; E-mail:
| | - John M. Clancy
- School of Pharmacy, Trinity College, Dublin 2, Ireland; E-mails: ;
| | - John F. Gilmer
- School of Pharmacy, Trinity College, Dublin 2, Ireland; E-mails: ;
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25
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26
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Aminosalicylic acid conjugates of EDTA as potential anti-inflammatory pro-drugs: synthesis, copper chelation and superoxide dismutase-like activities. TRANSIT METAL CHEM 2007. [DOI: 10.1007/s11243-007-9031-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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27
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Abstract
In this study, we examined the effectiveness of chitosan capsules for the colon-specific delivery of prednisolone in rats. We also evaluated the effectiveness and side effects of prednisolone using chitosan capsules compared with the conventional dosage form (gelatin capsules). We found a significant increase in the concentration of prednisolone in the large intestinal mucosa when prednisolone was administered orally using chitosan capsules, as compared with the case using gelatin capsules. On the other hand, the plasma concentrations of prednisolone after oral administration using chitosan capsules were much lower than those in the case of gelatin capsules. We also assessed the effectiveness of prednisolone for the healing of trinitrobenzene sulfonic acid-induced colitis by measuring myeloperoxidase (MPO) activity and colon wet weight/body weight (C/B) ratio. MPO activities and C/B ratios were significantly reduced when prednisolone was administered orally using chitosan capsules, in comparison with the case of gelatin capsules. Moreover, the weight of the thymus, which is an index of the side effects of prednisolone, markedly decreased after oral administration of prednisolone using gelatin capsules, whereas its weight did not change as much when prednisolone was administered orally using chitosan capsules. These findings indicate that chitosan capsules might be useful for the colon-specific delivery of prednisolone and its enhanced effectiveness for the healing of colitis in rats. Moreover, chitosan capsules might be also effective in reducing the side effects of prednisolone due to its decreased intestinal transfer to the systemic circulation.
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Affiliation(s)
- Akira Yamamoto
- Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
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28
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Jung Y, Kim HH, Kim H, Kong H, Choi B, Yang Y, Kim Y. Evaluation of 5-aminosalicyltaurine as a colon-specific prodrug of 5-aminosalicylic acid for treatment of experimental colitis. Eur J Pharm Sci 2006; 28:26-33. [PMID: 16455235 DOI: 10.1016/j.ejps.2005.12.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2005] [Revised: 10/06/2005] [Accepted: 12/12/2005] [Indexed: 01/16/2023]
Abstract
We previously reported that 5-aminosalicyltaurine (taurine-conjugated 5-ASA, 5-ASA-Tau) showed a potential as a colon-specific prodrug of 5-aminosalicylic acid (5-ASA) by in vitro evaluation. In this report, we in vivo-evaluated 5-ASA-Tau as a colon-specific prodrug for treatment of experimental colitis. Taurine conjugation of 5-ASA greatly reduced absorption of 5-ASA from the intestine. Oral administration of taurine-conjugated 5-ASA not only increased the colonic delivery efficiency of 5-ASA but also decreased the systemic absorption of free 5-ASA as compared with that of 5-ASA and, moreover, taurine is similarly effective to known colon-specific carriers for 5-ASA, glycine and aspartic acid, suggesting that taurine conjugation is an efficient way to increase the therapeutic effect and to reduce the adverse effects of 5-ASA. Intracolonic treatment with combined 5-ASA/taurine additively ameliorated TNBS-induced colitis rats indicating that taurine acted as not only a promoiety but also a therapeutically active agent. Furthermore, 5-ASA-Tau is slightly more effective than sulfasalazine in alleviating the colonic inflammation induced by TNBS. Taken together, our data suggest that 5-ASA-Tau is a potential colon-specific prodrug of 5-aminosalicylic acid with improved therapeutic activity against inflammatory bowel disease.
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Affiliation(s)
- Yunjin Jung
- Lab of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea
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29
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Zou MJ, Cheng G, Okamoto H, Hao XH, An F, Cui FD, Danjo K. Colon-specific drug delivery systems based on cyclodextrin prodrugs: in vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates. World J Gastroenterol 2006; 11:7457-60. [PMID: 16437716 PMCID: PMC4725178 DOI: 10.3748/wjg.v11.i47.7457] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the release of cyclodextrin-5-aminosalicylic acid (CyD-5-ASA) in cecum and colon. METHODS An anti-inflammatory drug 5-ASA was conjugated onto the hydroxyl groups of alpha-, beta- and gamma-cyclodextrins (CyDs) through an ester linkage, and the in vivo drug release behavior of these prodrugs in rat's gastrointestinal tract after the oral administration was investigated. RESULTS The 5-ASA concentration in the rat's stomach and small intestine after the oral administration of CyD-5-ASA conjugate was much lower than that after the oral administration of 5-ASA alone. The lower concentration was attributable to the passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specific in the cecum and colon. The oral administration of CyD-5-ASA resulted in lower plasma and urine concentration of 5-ASA than that of 5-ASA alone. CONCLUSION CyD-5-ASA conjugates may be used as prodrugs for colon-specific drug delivery system.
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Affiliation(s)
- Mei-Juan Zou
- School of Pharmacy, Shenyang Pharmaceutical University, Shenhe District, Shenyang 110016, Liaoning Province, China
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30
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Bourque TA, Nelles ME, Gullon TJ, Garon CN, Ringer MK, Leger LJ, Mason JW, Wheaton SL, Baerlocher FJ, Vogels CM, Decken A, Westcott SA. Late metal salicylaldimine complexes derived from 5-aminosalicylic acid Molecular structure of a zwitterionic mono Schiff base zinc complex. CAN J CHEM 2005. [DOI: 10.1139/v05-091] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Condensation of salicylaldehyde (2-HOC6H4C(O)H) with 5-aminosalicylic acid (5-H2NC6H3-2-(OH)-CO2H) afforded the Schiff base 2-HOC6H4C(H)=NC6H3-2-(OH)-5-CO2H (a). Similar reactivity with 5-bromosalicylaldehyde was also observed to give 5-Br-2-HOC6H3C(H)=NC6H3-2-(OH)-5-CO2H (b). Reaction of these salicylaldehydes with Pd(II), Cu(II), and Zn(II) salts gave the corresponding bis(N-arylsalicylaldiminato)metal complexes (M = Pd (1), Cu (2), Zn (3)). The molecular structure of the Schiff base compound a has been confirmed by an X-ray diffraction study. Crystals of a were monoclinic, space group P2(1)/c, a = 7.0164(7) Å, b = 11.0088(11) Å, c = 14.8980(15) Å, β = 102.917(2)°, Z = 4. The molecular structure of a novel zwitterionic conformer of 3a was also characterized by an X-ray diffraction study. Crystals of 4 were monoclinic, space group P2(1)/c, a = 9.5284(5) Å, b = 19.5335(11) Å, c = 8.6508(5) Å, β = 90.596(1)°, Z = 4. All new compounds have been tested for their antifungal activity against Aspergillus niger and Aspergillus flavus. Key words: 5-aminosalicylic acid (5-ASA), antifungal, copper, palladium, salicylaldimines, Schiff base, zinc.
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31
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Zou M, Okamoto H, Cheng G, Hao X, Sun J, Cui F, Danjo K. Synthesis and properties of polysaccharide prodrugs of 5-aminosalicylic acid as potential colon-specific delivery systems. Eur J Pharm Biopharm 2005; 59:155-60. [PMID: 15567313 DOI: 10.1016/j.ejpb.2004.06.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Accepted: 06/21/2004] [Indexed: 01/11/2023]
Abstract
The drug release of the polymer prodrugs of 5-aminosalicylic acid (5-ASA) was not only dependent on the property of the polymers but also dependent on the solubility of the prodrugs. We prepared several polysaccharide prodrugs of 5-ASA to examine the effect of solubility of prodrugs on the release characteristics of 5-ASA in the gastrointestinal contents of rats. The amide prodrug, chitosan-5-ASA (ChT-5-ASA), did not release the 5-ASA in the cecal and colonic contents. The ester prodrugs, hydroxypropyl cellulose-5-ASA (HPC-5-ASA), being poor solubility in 0.05mol/l acetic acid solution also did not release the 5-ASA in any of gastrointestinal contents of rats. Whereas the 5-ASA release from cyclodextrins-5-ASA (CyDs-5-ASA) in cecal and colonic contents was significantly higher than that in stomach and small intestine contents. And furthermore, with the decrease in the degree of substitution, the solubility of CyD-5-ASA increased, and the release of 5-ASA in the gastrointestinal contents was also higher at the same time interval of incubation. When the ratio of cyclodextrin (CyD) and 5-formylaminosalicylic acid (5-fASA), a precursor of 5-ASA prodrugs, was 1:10, CyD-5-ASA was very slightly soluble, and no release of 5-ASA was observed within 48h in gastrointestinal contents. The present results suggested that the ester prodrugs of 5-ASA with certain solubility could release 5-ASA in the cecal and colonic contents of rat.
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Affiliation(s)
- Meijuan Zou
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
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32
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Bailey MA, Ingram MJ, Naughton DP. A novel anti-oxidant and anti-cancer strategy: a peptoid anti-inflammatory drug conjugate with SOD mimic activity. Biochem Biophys Res Commun 2004; 317:1155-8. [PMID: 15094390 DOI: 10.1016/j.bbrc.2004.03.162] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2004] [Indexed: 11/21/2022]
Abstract
Activation of reactive oxygen and nitrogen species (RONS) by redox-active metal ions has been proposed to contribute to oxidative damage in inflamed tissues. Here, we report a dual-function anti-oxidant conjugate comprising an anti-inflammatory agent (5-aminosalicylic acid) and a chelator with potential as a superoxide dismutase mimic. The conjugate ethylenediaminetetraacetic acid bis-(5-aminosalicylic acid methyl ester) [EBAME] chelates Cu(II) ions in a 1:1 ratio, as assessed spectrophotometrically using Job's method. Superoxide dismutase (SOD) activity was determined for the Mn(II)-conjugate as 0.758+/-0.130 U at a concentration of 0.99 microM. In inflamed tissues, peptidase mediated release of active 5-ASA would also release the EDTA chelator which has significant SOD mimic activity when complexed to Cu(II) ions. Thus, EBAME has potential as a dual-function anti-inflammatory agent with reduced gastric irritability.
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Affiliation(s)
- Mark A Bailey
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Moulsecoomb, Brighton BN2 4GJ, UK
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Jung YJ, Doh MJ, Kim IH, Kong HS, Lee JS, Kim YM. Prednisolone 21-sulfate sodium: a colon-specific pro-drug of prednisolone. J Pharm Pharmacol 2003; 55:1075-82. [PMID: 12956896 DOI: 10.1211/0022357021413] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Prednisolone 21-sulfate sodium (PDS) was synthesized as a colon-specific pro-drug of prednisolone with the expectation that it would be stable and non-absorbable in the upper intestine and release prednisolone by the action of sulfatase once it was delivered to the colon. In-vitro/in-vivo properties were investigated using rats as test animals. PDS was chemically stable at pH 1.2, 4.5, 6.8 and 8.0, and the apparent partition coefficient was 0.11 in 1-octanol/pH 6.8 buffer solution at 37 degrees C. PDS was stable on incubation with the contents of the stomach or small intestine. When PDS (0.1 mg equiv. of prednisolone) was incubated with the caecal contents (0.05 g), prednisolone was produced to a maximum 54% of the dose in 6 h and decreased thereafter, which suggested that reduction of the A ring took place in addition to the hydrolysis by sulfatase. After oral administration of PDS, a small portion of prednisolone was recovered from the cecal contents but not from the small intestine. Neither PDS nor prednisolone was detected in the plasma, suggesting that absorption of PDS is limited. The data demonstrate that the sulfate ester can serve as a novel colon-specific pro-moiety by limiting the absorption of the pro-drug in the upper intestine and releasing the active compound by the action of microbial sulfatase in the colon.
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Affiliation(s)
- Yun Jin Jung
- College of Pharmacy, Pusan National University, Pusan 609-735, Korea
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34
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Jung YJ, Kim HH, Kong HS, Kim YM. Synthesis and properties of 5-aminosalicyl-taurine as a colon-specific prodrug of 5-aminosalicylic acid. Arch Pharm Res 2003; 26:264-9. [PMID: 12735682 DOI: 10.1007/bf02976953] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
5-Aminosalicylic acid (5-ASA) is an active ingredient of therapeutic agents used for Crohn's disease and ulcerative colitis. Because it is absorbed rapidly and extensively in the upper intestine, delivery of the agent specifically to the colon is necessary. We selected taurine as a colon-specific promoiety and designed 5-aminosalicyltaurine (5-ASA-Tau) as a new colon-specific prodrug of 5-aminosalicylic acid (5-ASA). It was expected that introduction of taurine would restrict the absorption of the prodrug and show additive effect to the anti-inflammatory action of 5-ASA after hydrolysis. 5-ASA-Tau was prepared in good yield by a simple synthetic route. The apparent partition coefficient of 5-ASA-Tau in 1-octanol/pH 6.8 phosphate buffer or CHCl3/pH 6.8 phosphate buffer was 0.10 or 0.18, respectively, at 37 degrees C. To determine the chemical and biochemical stability in the upper intestinal environment, 5-ASA-Tau was incubated in pH 1.2 and 6.8 buffer solutions, and with the homogenates of tissue and contents of stomach or small intestine of rats at 37 degrees C. 5-ASA was not detected from any of the incubation medium with no change in the concentration of 5-ASA-Tau. On incubation of 5-ASA-Tau with the cecal and colonic contents of rats, the fraction of the dose released as 5-ASA was 45% and 20%, respectively, in 8 h. Considering low partition coefficient and stability in the upper intestine, 5-ASA-Tau might be nonabsorbable and stable in the upper intestine. After oral administration, it would be delivered to the colon in intact form and release 5-ASA and taurine. These results suggested 5-ASA-Tau as a promising colon-specific prodrug of 5-ASA.
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Affiliation(s)
- Yun Jin Jung
- College of Pharmacy, Pusan National University, Pusan 609-735, Korea
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35
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Doh MJ, Jung YJ, Kim IH, Kong HS, Kim YM. Synthesis and in vitro properties of prednisolone 21-sulfate sodium as a colon-specific prodrug of prednisolone. Arch Pharm Res 2003; 26:258-63. [PMID: 12735681 DOI: 10.1007/bf02976952] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Colon-specific delivery of glucocorticoids is highly desirable for the efficient treatment of inflammatory bowel disease. We synthesized prednisolone 21-sulfate sodium (PDS) as a colon-specific prodrug of prednisolone (PD) and investigated its properties using rats as test animals. We expected that introduction of sulfate ester as a sodium salt might increase the hydrophilicity and restrict the absorption in the GI tract. If PDS is stable and nonabsorbable in the upper intestine, it will be delivered to the colon as an intact form, where it hydrolyze by the sulfatase to release PD. Compared with PD, the solubility of PDS increased and the apparent partition coefficient decreased greatly. PDS was stable on incubation with pH 1.2 and 6.8 buffer solutions and with the contents of the stomach and small intestine. On incubation with the cecal contents, PDS decreased to 9.6% of the dose in 10 h producing PD. The amount of PD increased to give a maximum 54% of the dose and decreased. As a control, when PD was incubated with the cecal contents, it decreased to 29% of the dose in 8 h, which implied that reduction of PD proceeded under such conditions. These results suggested that hydrolysis of PDS took place to produce and accumulate PD, which decreased by reduction as the incubation period extended. Our results suggested that PDS can be a promising colon-specific prodrug of PD, and sulfate ester group might serve as a potential colon-specific promoiety, especially for the drugs which are resistant to reduction in the colon.
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Affiliation(s)
- Min Ju Doh
- College of Pharmacy, Pusan National University, Pusan 609-735, Korea
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Pang YN, Zhang Y, Zhang ZR. Synthesis of an enzyme-dependent prodrug and evaluation of its potential for colon targeting. World J Gastroenterol 2002; 8:913-7. [PMID: 12378641 PMCID: PMC4656586 DOI: 10.3748/wjg.v8.i5.913] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To synthesize dexamethasone-succinate-dextran (DSD) conjugate and to evaluate the potentiality of DSD for the treatment of inflammatory bowel diseases.
METHODS: Dexamethasone was attached to dextran (average molecular weight = 70400 Dalton) using succinate anhydride in an anhydrous environment catalyzed by 4-dimethylaminopyridine and 1,1’-carbonyldiimidazole. The chemical structure of DSD was identified by UV, IR and NMR, and the in vivo drug release behavior of this prodrug was investigated after oral administration of DSD suspension.
RESULTS: The DSD conjugate was obtained in two steps and the content of dexamethasone in DSD was 11.28%. The dextran prodrug was stable in rat stomach and small intestine and negligibly absorbed from these tracts. Four to nine hours after the oral administration, most of the prodrug (> 95%) had moved to the cecum and colon, and was easily hydrolyzed by an endodextranase. Recover of dexamethasone from colon and cecum after administration of DSD conjugate was 6-12 folds higher than the recovery after administration of unmodified dexamethasone (t = 2.74, P < 0.05). The preferential release of free dexamethasone in cecum and colon over that in the small intestine was statistically significant (t = 2.27, P < 0.05).
CONCLUSION: The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the colon.
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Affiliation(s)
- Yi-Nuo Pang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, Sichuan Province, China
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