title: Biodistribution of diclofenac following repeated topical applications of two diclofenac sodium formulations to minipigs.
abstract: This study evaluated diclofenac concentrations in plasma, selected hind limb tissues and synovial fluid after repeated topical applications of two diclofenac formulations. Group 1 Gottingen minipigs (n = 18) were administered diclofenac sodium 2.0% topical solution twice daily on days 1-6 and once on day 7. Group 2 minipigs (n = 18) were administered diclofenac sodium 1.5% topical solution four times daily on days 1-6 and twice on day 7. Approximately 20 mg of diclofenac was applied daily to a 10 × 15 cm dosing site centered over the patella of the right knee. Plasma and tissue samples were collected throughout and analysed for diclofenac concentrations using liquid chromatography with tandem mass spectrometry. On day 1, diclofenac sodium 2.0% topical solution produced higher plasma concentrations compared with the 1.5% formulation; however, after 24 h and throughout the remainder of the dosing period, plasma concentrations appeared similar, except at the 72 h time point. Twenty-four hours after the final application, skin treated with diclofenac sodium 2.0% topical solution retained a significantly (p < 0.02) greater amount of diclofenac than the 1.5% formulation. Generally, both formulations produced similar diclofenac concentrations in synovial fluid, underlying muscle, tendon and bone 24 h after the last application. The 2.0% diclofenac formulation applied twice daily delivered similar amounts of diclofenac as the 1.5% formulation administered four times daily. The skin retained a significant portion of the applied dose to serve as a depot for continuous diffusion of diclofenac into underlying tissues and systemic circulation.
authors.affiliation: Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Wible
authors.forename: Thomas
authors.initials: T
authors.lastname: Barrett
authors.forename: Krishna
authors.initials: K
authors.lastname: Devarakonda
authors.forename: Michael
authors.initials: M
authors.lastname: Giuliani
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D001842:Bone and Bones / Q000378:metabolism; D004008:Diclofenac / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D035002:Lower Extremity; D018482:Muscle, Skeletal / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D013582:Synovial Fluid / Q000378:metabolism; D013710:Tendons / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac
keywords: biodistribution; diclofenac; knee; osteoarthritis; topical