In vitro based index of topical anti-inflammatory activity to compare a series of NSAIDs.
The aim of the present work was to generate an index to predict topical efficiency of a series of nonsteroidal anti-inflammatory drugs (NSAIDs): indomethacin, diclofenac, ketoprofen, piroxicam, tenoxicam and ketorolac. This index took into account both biopharmaceutic and pharmacodynamic aspects. The biopharmaceutic aspect, based on the maximal flux (J(m)), was determined experimentally from transdermal studies carried out with human skin in previous work. The pharmacodynamic aspect, based on the ability to inhibit cyclooxygenase-2 (COX-2) in vitro, was determined by incubating human dermal fibroblasts in culture, pre-treated with phobol-12-myristate-13-acetate (PMA) for 6 h, with 25 microM [(14)C]-arachidonic acid (AA) in the presence of several drug concentrations. The most potent inhibitor of COX-2 activity in induced fibroblasts was diclofenac while indomethacin, ketoprofen and ketorolac were approximately equipotent. Piroxicam and tenoxicam were inhibitors at higher concentrations. Based on the proposed index of the topical anti-inflammatory activity (ITAA) diclofenac, ketorolac, ketoprofen and indomethacin exhibited acceptable efficiency for external use. However, piroxicam and tenoxicam showed the lowest topical anti-inflammatory activity of the series assayed. In conclusion, indomethacin ketorolac, ketoprofen and diclofenac have shown good intrinsic feasibility for formulation into topical pharmaceutical forms. However, for dermatological formulations of oxicams, use of penetration enhancers may be unavoidable.
Cordero
J A
JA
Pharmacokinetics and Biopharmaceutics Unit, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII, s/n, 08028-Barcelona, Spain.
Camacho
M
M
Obach
R
R
Domenech
J
J
Vila
L
L
D000287:Administration, Topical; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate