Evaluation of dextran-flufenamic acid ester as a polymeric colon-specific prodrug of flufenamic acid, an anti-inflammatory drug, for chronotherapy.
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.
Lee
Yonghyun
Y
College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Kim
In Ho
IH
Kim
Jeongyun
J
Yoon
Jeong-Hyun
JH
Shin
Young Hee
YH
Jung
Yunjin
Y
Kim
Young Mi
YM
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002432:Cecum / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000378:metabolism*; D003692:Delayed-Action Preparations; D003911:Dextrans / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055870:Drug Chronotherapy; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004355:Drug Stability; D005439:Flufenamic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D010437:Peptic Ulcer / Q000139:chemically induced / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003692:Delayed-Action Preparations; D003911:Dextrans; D011355:Prodrugs; C560742:dextran-flufenamic acid ester; D005439:Flufenamic Acid