Abstract
Dextran-flufenamic acid ester (Dex-FFA) with varied degree of substitution (DS) was prepared by imidazolide method. Dex-FFA was stable in pH 1.2 or pH 6.8 buffer. The depolymerization degree of Dex-FFA by dextranase decreased as DS increased. Dex-FFA with DS of 13 or 20 released FFA up to 70% or 21% of the dose, respectively, on 24 h-incubation with the 10% cecal contents. FFA was liberated up to 29% of the dose on 24 h-incubation of dextranase pre-treated Dex-FFA with the homogenates of the upper intestine, whereas no FFA was detected devoid of dextranse-pretreatment. Upon oral administration of Dex-FFA (DS 13, 20 mg equivalent of FFA/kg) or FFA (10 mg/kg) to rats, t(max) for FFA with Dex-FFA administration delayed approximately 6 h compared with that of free FFA administration, while C(max) for FFA was similar. The plasma level for FFA became greater around 6 h after administration of Dex-FFA than free FFA and it was maintained throughout the period of 24 h-experiment. Dex-FFA markedly attenuated gastric ulcerogenicity of FFA. Taken together, Dex-FFA could be useful as a colon-specific prodrug which possesses anti-inflammatory properties and offers opportunities as a chronotherapeutic approach for the treatment of arthritis.
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / administration & dosage*
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Anti-Inflammatory Agents, Non-Steroidal / adverse effects
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cecum / metabolism
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Chromatography, High Pressure Liquid
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Colon / metabolism*
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Delayed-Action Preparations
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Dextrans / administration & dosage
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Dextrans / adverse effects
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Dextrans / pharmacokinetics
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Dextrans / pharmacology*
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Drug Chronotherapy
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Drug Compounding
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Drug Delivery Systems
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Drug Stability
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Flufenamic Acid / administration & dosage
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Flufenamic Acid / adverse effects
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Flufenamic Acid / analogs & derivatives*
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Flufenamic Acid / pharmacokinetics
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Flufenamic Acid / pharmacology
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Gastric Mucosa / drug effects
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Gastric Mucosa / pathology
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Hydrogen-Ion Concentration
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / pathology
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Male
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Molecular Structure
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Peptic Ulcer / chemically induced
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Peptic Ulcer / pathology
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Prodrugs / administration & dosage*
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Prodrugs / adverse effects
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Solubility
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Spectrophotometry, Ultraviolet
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Tissue Distribution
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Delayed-Action Preparations
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Dextrans
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Prodrugs
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dextran-flufenamic acid ester
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Flufenamic Acid