Glycolamide esters as a novel biolabile prodrug type for non-steroidal anti-inflammatory carboxylic acid drugs

Bundgaard, Hans; Nielsen, Niels Mørk

doi:10.1016/0378-5173(88)90064-6

Cited by 51 publications

(15 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acetylsalicylic acid and most newer NSAI drugs are carboxylic acids. Temporary masking of the acid function has been proposed as a promising means of reducing gastro -intestinal toxicity due to the direct mucosal contact mechanism (8).…”

Section: Inprovement Of Gastro-intestinal Tolerancementioning

confidence: 99%

Prodrugs for the improvement of drug absorption via different routes of administration

Balant

Doelker

Buri

1990

Eur. J. Drug Metab. Pharmacokinet.

View full text Add to dashboard Cite

The authors critically review recent knowledge on the use of prodrugs to improve drug absorption. Main emphasis is placed on the parenteral, oral, transdermal and ocular routes. Mechanisms for drug absorption enhancement and bioavailability assessment are discussed. Some other applications of prodrugs are also examined. Finally, some comments are made regarding the present situation and future trends in prodrug design and their implications in biopharmaceutics and pharmacokinetics.

show abstract

Section: Inprovement Of Gastro-intestinal Tolerancementioning

confidence: 99%

Prodrugs for the improvement of drug absorption via different routes of administration

Balant

Doelker

Buri

1990

Eur. J. Drug Metab. Pharmacokinet.

View full text Add to dashboard Cite

show abstract

“…This enhanced gastric motility leads to reduction in mucosal blood flow, hypoxia, and destruction of mucous bicarbonate barrier, which prevents back diffusion of pepsin and hydrogen ions from lumen into the mucosal layer (Takeuchi, 1989). The GI side effects produced by NSAIDs are principally caused by two different mechanisms: a direct contact mechanism on the GI mucosa through oral dose and a generalized systemic action appearing after intravenous dosing (Bundgaard and Nielsen, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…The esters being pharmacologically inactive get readily hydrolyzed followed by their absorption to release parent drug in the blood. These esters should also possess desirable physicochemical properties such as aqueous solubility and lipophilicity (Bundgaard and Nielsen, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…(Bundgaard and Nielsen, 1988;Giammona et al, 1989;Otero Espinar et al, 1991;Chang and Tsai, 1997;Chang et al, 1998;Rautio et al, 2000;Bonina et al, 2001;Sheha et al, 2002;Khan and Khan, 2002;Chang et al, 2004;Swart et al, 2005;Ranatunge et al, 2006;Bhushan and Tanwar, 2008;Stefanko et al, 2008). Moreover, conjugation with amino acid such as L-aspartic acid has also been studied (El-Kamel et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and evaluation of novel prodrugs of naproxen

et al. 2010

View full text Add to dashboard Cite

A series of novel prodrugs of naproxen has been synthesized. Naproxen (1) was reacted with thionyl chloride to yield acid chloride (2) which was further reacted with glucose to form the glucosyl naproxen (3). Tetra-acetate of glucosyl naproxen was prepared and finally reacted with different amino acids to yield the title compounds. These compounds were evaluated for analgesic, anti-inflammatory activities, and for possible GI toxicity. Compound 5b depicted most potent analgesic activity with percentage inhibition of 98.15%. Compound 5a was found to be most potent anti-inflammatory agent with 76% inhibition. Compound 5n was second most active analgesic (92.26%) and anti-inflammatory (73%) agent. In vitro hydrolysis pattern of synthesized prodrugs was studied in phosphate buffer of pH 7.4 and acetate buffers of pH 3.0, 4.0, and 5.0, respectively. Selected compounds were evaluated for their ulcerogenic potential and all the tested derivatives were significantly less irritating to gastric mucosa than the parent drug.

show abstract

“…However several reports stated that large overdoses of paracetamol can produce a fulminant hepatic and renal tubular necrosis due to formation of the toxic metabolite, N-acetyl-p-benzoquinoneimine, NAPQI, 2 [6,7]. Ester prodrug forms have been shown to be one of the effective mechanisms that markedly reduce the ulcerogenic side-effects of some potent NSAIDs [8][9][10][11]. In addition, it has been reported that the aforementioned induced hepatotoxicity of paracetamol can be prevented through ester prodrug formation [12,13].…”

Section: Introductionmentioning

confidence: 99%

Paracetamol (acetaminophen) esters of some non-steroidal anti-inflammatory carboxylic acids as mutual prodrugs with improved therapeutic index

Fadl

Omar

1998

Inflammopharmacol

View full text Add to dashboard Cite

Paracetamol (acetaminophen) esters [4a-f] of some acidic NSAIDs were synthesized and evaluated as mutual prodrug forms with the aim of improving the therapeutic index through prevention of the gastrointestinal toxicity. The structures of the synthesized esters were confirmed by IR and (1)H-NMR spectroscopy and their purity was established by elemental analyses and TLC. In-vitro stability studies revealed that the synthesized ester prodrugs 4a-f are sufficiently chemically stable in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3 (t (1/2) approximately 15-45 h)) and in phosphate buffer of pH 7.4 (t (1/2) approximately 4-40 h). In 80% human plasma and 10% rat liver homogenate, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis releasing the corresponding NSAID and paracetamol at relatively faster rates (t (1/2) approximately 15-385 min and 1-140 min, respectively). Calculated log P values indicated that the prodrugs 4a-f are more lipophilic than the parent drugs.In-vivo experiments in rabbits showed higher plasma levels of ibuprofen after oral administration of its ester prodrug 4b compared with those resulting from an equivalent amount of the corresponding physical mixture. Moreover, significant improvement in latency of pain threshold in mice has been observed up to 4 h after po administration of 0.02 mmol/kg of the prodrugs, compared with the corresponding physical mixtures. Gross observations and scanning electromicrographs of the stomach showed that the prodrugs induced very little irritancy in the gastric mucosa of mice after oral administration for 4 days. These results suggest that the synthesized mutual ester prodrugs were characterized by a better therapeutic index than the parent drugs.

show abstract

Glycolamide esters as a novel biolabile prodrug type for non-steroidal anti-inflammatory carboxylic acid drugs

Cited by 51 publications

References 17 publications

Prodrugs for the improvement of drug absorption via different routes of administration

Prodrugs for the improvement of drug absorption via different routes of administration

Synthesis and evaluation of novel prodrugs of naproxen

Paracetamol (acetaminophen) esters of some non-steroidal anti-inflammatory carboxylic acids as mutual prodrugs with improved therapeutic index

Contact Info

Product

Resources

About