Gastrointestinal Toxicity, Antiinflammatory Activity, and Superoxide Dismutase Activity of Copper and Zinc Complexes of the Antiinflammatory Drug Indomethacin

• Published in: Chemical research in toxicology Vol. 16; no. 1; pp. 28 - 37
• Main Authors: Dillon, Carolyn T, Hambley, Trevor W, Kennedy, Brendan J, Lay, Peter A, Zhou, Qingdi, Davies, Neal M, Biffin, J. Ray, Regtop, Hubert L
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.01.2003
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Carrageenan - pharmacology; Cecum - chemistry; Cecum - drug effects; Cecum - metabolism; Copper - chemistry; Copper - metabolism; Edema - chemically induced; Edema - pathology; Electron Spin Resonance Spectroscopy; Hemoglobins - analysis; Hemoglobins - metabolism; Hindlimb - drug effects; Hindlimb - pathology; indomethacin; Indomethacin - chemistry; Indomethacin - metabolism; Indomethacin - toxicity; Male; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - toxicity; Rats; Rats, Sprague-Dawley; Superoxide Dismutase - metabolism; Ulcer - chemically induced; Ulcer - pathology; Zinc - chemistry; Zinc - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx020078o

Gastrointestinal (GI) toxicity is one of the major problems associated with antiinflammatory drugs. The complexation of the powerful antiinflammatory drug (IndoH) by metal ions, as a means of reducing GI toxicity, has been studied. The in vitro superoxide dismutase (SOD) activity, in vivo antiinflammatory activity, and gastrointestinal ulcerogenic properties of IndoH, [Cu2(Indo)4(DMF)2], and [Zn2(Indo)4(DMA)2] are reported. No SOD activity was observed for IndoH or [Zn2(Indo)4(DMA)2], but [Cu2(Indo)4(DMF)2] inhibited the reduction of nitroblue tetrazolium (NBT) at an IC50 value of 0.23 μM. All three compounds exhibited antiinflammatory activity in male Sprague−Dawley rats at an equivalent Indo dose of 10 mg/kg following oral administration of the drugs in 2% CMC solution. The severity of the toxicity (macroscopic ulcerations) in the stomach following oral dosing with [Zn2(Indo)4(DMF)2] was not significantly lower than that induced by IndoH (P = 0.78). Gastric ulcerations induced by [Cu2(Indo)4(DMF)2] were significantly lower than those induced by IndoH or [Zn2(Indo)4(DMA)2] (P = 0.0012 and P = 0.0175, respectively) but significantly greater than the control (P = 0.0013). The intestinal ulcerations induced by [Cu2(Indo)4(DMF)2] or [Zn2(Indo)4(DMA)2] were approximately 15 times lower than those of IndoH. A further indicator of gastrointestinal toxicity, caecal haemoglobin, increased in the following order:  control < [Cu2(Indo)4(DMF)2] < [Zn2(Indo)4(DMA)2] < IndoH. [Cu2(Indo)4(DMF)2] exhibited the most promising results of the Indo complexes assayed, in that it exhibited SOD activity and the lowest gastrointestinal damage while also exhibiting antiinflammatory activity that was comparable to that for IndoH. Low-temperature EPR analyses also showed that the formulation used for [Cu2(Indo)4(DMF)2] administration was crucial to the integrity of the complex.