Synthesis and Evaluation of N-Nicotinoyl-2-{2-(2-Methyl-5-Nitroimidazol-1-yl)Ethyloxy}-D,L-Glycine as a Colon-Specific Prodrug of Metronidazole

Kim, Duksoo; Hong, Sungchae; Jung, Sang-Don; Jung, Yunjin; Kim, Young Mi

doi:10.1002/jps.21720

Cited by 11 publications

(10 citation statements)

References 23 publications

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“…However, this is not a very flexible method because it relies on the functional groups of the drug molecule (4). Kim et al synthesized a prodrug of metronidazole, which was metabolized to the active drug, metronidazole when placed in rats' cecal contents (39). Unlike metronidazole, this prodrug did not metabolize in the small intestine, and the systemic absorption of this prodrug was also found to be much lower compared to that of oral metronidazole (39).…”

Section: Conventional Approaches For Achieving Colonic Delivery Prodrugsmentioning

confidence: 99%

“…Kim et al synthesized a prodrug of metronidazole, which was metabolized to the active drug, metronidazole when placed in rats' cecal contents (39). Unlike metronidazole, this prodrug did not metabolize in the small intestine, and the systemic absorption of this prodrug was also found to be much lower compared to that of oral metronidazole (39). In another study, Kim et al prepared a prodrug of metronidazole, using a sulfate group, and showed that that this formulation remained intact in the upper intestine, but was cleaved in the presence of rat cecal contents and active metronidazole was released.…”

Section: Conventional Approaches For Achieving Colonic Delivery Prodrugsmentioning

confidence: 99%

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Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches

2015

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Abstract. Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

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Section: Conventional Approaches For Achieving Colonic Delivery Prodrugsmentioning

confidence: 99%

Section: Conventional Approaches For Achieving Colonic Delivery Prodrugsmentioning

confidence: 99%

Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches

2015

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“…The structure of the product was confirmed from the data of IR and 1 H-NMR spectra and the results from the elemental analysis. Compounds used for the present study include N-benzoyl-glycine (1), N-benzoyl-Lalanine (2), N-benzoyl-D-alanine (3), N-benzoyl-D, L-alanine (4), N-benzoyl-b-alanine (5), N-benzoyl-L-phenylalanine (6), N-benzoyl-D-phenylalanine (7) N-benzoyl-D,L-phenylalanine (8), N-benzoylglycyl-D,L-phenylalanine (9), N-(4-methylbenzoyl)-glycine (10), N-(2-methylbenzoyl)-glycine (11), N-(2-chlorobenzoyl)-glycine (12), N-(4-chlorobenzoyl)-glycine (13), N-(2-hydroxybenzoyl) -glycine (14), N-(4-aminobenzoyl)-glycine (15), N-(4-nitrobenzoyl)-glycine (16), N-(4-methoxybenzoyl)-glycine (17), N-(2-methoxybenzoyl)-glycine (18), N-benzoyl-4-aminobutyric acid (19), N-benzoyl-aminomethanesulfonic acid (20), N-benzoyl-2-aminoethanesulfonic acid (21) and N-benzoyl-3 -aminopropanesulfonic acid (22). The structures of the above compounds are shown in Figure 2.…”

Section: Preparation Of N-aromatic Acyl-amino Acid Conjugatesmentioning

confidence: 99%

“…The NFG was designed as a colon-specific prodrug of 5-fluorouracil because 2-(5-fluorouracil-1-yl)-glycine, which is formed after the cleavage of the amide bond in NFG in the cecal contents, decomposes spontaneously to release 5-fluorouracil [17]. Substitution of other drug with a nucleophile should produce a compound with a general structure of Naromatic acyl-2-(drug)-glycine, which can be a colon-specific prodrug [18]. In this case, Naromatic acyl-glycine acts as a colon-specific promoiety and bioactivation of the prodrug depends on the hydrolysis of the amide bond in the colon.…”

Section: Introductionmentioning

confidence: 99%

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

Kong

Kim

et al. 2011

Biopharm & Drug Disp

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N-aromatic acyl-amino acid conjugates possess a colon-targeted property, implying that such conjugates are stable and are not absorbable until reaching the large intestine in which they are microbially converted (hydrolysed) to the parent drugs that are therapeutically active. To investigate the structural effect of N-aromatic acyl-amino acid conjugates on the large intestinal deconjugation, the hydrolysis of various N-aromatic acyl-amino acid conjugates was examined in the cecal contents. On incubation of conjugates with glycine, D or/and L forms of alanine or phenylalanine in the cecal contents, the conjugates with D amino acids were not hydrolysed. The other conjugates are susceptible to the hydrolysis, the rates of which decreased as the size of the substituent on the 2-position of the amino acids increased. The conjugates with alkyl analogs (2-4 carbons) of glycine and taurine were resistant to the hydrolysis, while taurine- and glycine-conjugates were hydrolysed effectively. The hydrolysis of N-aromatic acyl-glycine conjugates was enhanced by para-substitution of electron withdrawing groups on the aromatic acyl moiety and vice versa for electron-donating groups. While a methyl, methoxy or chloro group on the ortho-position retarded the hydrolysis, a hydroxyl group on the position accelerated it. Our data may provide useful information for the design of a colon-specific prodrug with controlled conversion rate in the large intestine.

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“… 5 – 7 For this purpose, two kinds of colon-specific prodrugs have been developed – MTDZ sulfate and N -nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}- d , l -glycine (NMG). 8 , 9 However, these colon-specific prodrugs do not seem to distribute MTDZ to the entire large intestine. Previous studies demonstrated that neither MTDZ nor the prodrugs were detected in the colon, but that the prodrugs were found in the cecum.…”

Section: Introductionmentioning

confidence: 99%

Conjugation of metronidazole with dextran: a potential pharmaceutical strategy to control colonic distribution of the anti-amebic drug susceptible to metabolism by colonic microbes

Kim¹,

Yang²,

Kim³

et al. 2017

DDDT

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Metronidazole (MTDZ), the drug of choice for the treatment of protozoal infections such as luminal amebiasis, is highly susceptible to colonic metabolism, which may hinder its conversion from a colon-specific prodrug to an effective anti-amebic agent targeting the entire large intestine. Thus, in an attempt to control the colonic distribution of the drug, a polymeric colon-specific prodrug, MTDZ conjugated to dextran via a succinate linker (Dex-SA-MTDZ), was designed. Upon treatment with dextranase for 8 h, the degree of Dex-SA-MTDZ depolymerization (%) with a degree of substitution (mg of MTDZ bound in 100 mg of Dex-SA-MTDZ) of 7, 17, and 30 was 72, 38, and 8, respectively, while that of dextran was 85. Depolymerization of Dex-SA-MTDZ was found to be necessary for the release of MTDZ, because dextranase pretreatment ensures that de-esterification occurs between MTDZ and the dextran backbone. In parallel, Dex-SA-MTDZ with a degree of substitution of 17 was found not to release MTDZ upon incubation with the contents of the small intestine and stomach of rats, but it released MTDZ when incubated with rat cecal contents (including microbial dextranases). Moreover, Dex-SA-MTDZ exhibited prolonged release of MTDZ, which contrasts with drug release by small molecular colon-specific prodrugs, MTDZ sulfate and N-nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}-d,l-glycine. These prodrugs were eliminated very rapidly, and no MTDZ was detected in the cecal contents. Consistent with these in vitro results, we found that oral gavage of Dex-SA-MTDZ delivered MTDZ (as MTDZ conjugated to [depolymerized] dextran) to the distal colon. However, upon oral gavage of the small molecular prodrugs, no prodrugs were detected in the distal colon. Collectively, these data suggest that dextran conjugation is a potential pharmaceutical strategy to control the colonic distribution of drugs susceptible to colonic microbial metabolism.

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Synthesis and Evaluation of N-Nicotinoyl-2-{2-(2-Methyl-5-Nitroimidazol-1-yl)Ethyloxy}-D,L-Glycine as a Colon-Specific Prodrug of Metronidazole

Cited by 11 publications

References 23 publications

Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches

Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches

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

Conjugation of metronidazole with dextran: a potential pharmaceutical strategy to control colonic distribution of the anti-amebic drug susceptible to metabolism by colonic microbes

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