Oligoethylene ester derivatives of ketoprofen, naproxen and diclofenac as oral prodrugs: a pharmacological evaluation.
Polyoxyethylene esters of ketoprofen (1a-e), naproxen (2a-e) and diclofenac (3a-e) were tested in vitro to determine their stability in pH 7.4 phosphate buffer and in simulated gastric fluid (pH 2.0 buffer) and their susceptibility in undergoing enzymatic cleavage in human plasma. Furthermore their in vivo antiinflammatory and analgesic activity and GI toxicity were evaluated in rodents. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer. They were readily hydrolyzed by human plasma and, for each group of prodrugs, no significant difference in hydrolysis rate was observed as the length of the oligoethylene chain increased. Esters 1a-e, 2a-e and 3a-e showed an anti-inflammatory activity (expressed as inhibition percent of carrageenan-induced edema in the rat) similar to that of their respective parent drug although at higher doses. The results obtained in the writhing test in mice demonstrated that all the prodrugs tested exhibited, following acute administration, a good analgesic effect. Furthermore these esters were significantly less irritating to the gastric mucosa, although administered at doses higher than the respective parent drug.
Bonina
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F
Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Italy. boninaf@mbox.unict.it
Puglia
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C
Santagati
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NA
Saija
A
A
Tomaino
A
A
Tita
B
B
D019342:Acetic Acid; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002351:Carrageenan; D004008:Diclofenac / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004952:Esters; D006868:Hydrolysis; D007660:Ketoprofen / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D009288:Naproxen / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D010147:Pain Measurement / Q000187:drug effects; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D011355:Prodrugs / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D014677:Pharmaceutical Vehicles; D011355:Prodrugs; D004008:Diclofenac; D011092:Polyethylene Glycols; D009288:Naproxen; D002351:Carrageenan; D007660:Ketoprofen; D019342:Acetic Acid