Gastrointestinal Toxicity, Antiinflammatory Activity, and Superoxide Dismutase Activity of Copper and Zinc Complexes of the Antiinflammatory Drug Indomethacin
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- 作者：Carolyn T. Dillon ; Trevor W. Hambley ; Brendan J. Kennedy ; Peter A. Lay ; Qingdi Zhou ; Neal M. Davies ; J. Ray Biffin ; and Hubert L. Regtop
- 刊名：Chemical Research in Toxicology
- 出版年：2003
- 出版时间：January 2003
- 年：2003
- 卷：16
- 期：1
- 页码：28 - 37
- 全文大小：161K
- 年卷期：v.16,no.1(January 2003)
- ISSN：1520-5010
文摘
Gastrointestinal (GI) toxicity is one of the major problems associated with antiinflammatorydrugs. The complexation of the powerful antiinflammatory drug (IndoH) by metal ions, as ameans 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 forIndoH or [Zn2(Indo)4(DMA)2], but [Cu2(Indo)4(DMF)2] inhibited the reduction of nitrobluetetrazolium (NBT) at an IC50 value of 0.23 
mages/entities/mgr.gif">M. All three compounds exhibited antiinflammatoryactivity in male Sprague-Dawley rats at an equivalent Indo dose of 10 mg/kg following oraladministration of the drugs in 2% CMC solution. The severity of the toxicity (macroscopiculcerations) in the stomach following oral dosing with [Zn2(Indo)4(DMF)2] was not significantlylower 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 andP = 0.0175, respectively) but significantly greater than the control (P = 0.0013). The intestinalulcerations induced by [Cu2(Indo)4(DMF)2] or [Zn2(Indo)4(DMA)2] were approximately 15 timeslower 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, inthat it exhibited SOD activity and the lowest gastrointestinal damage while also exhibitingantiinflammatory activity that was comparable to that for IndoH. Low-temperature EPRanalyses also showed that the formulation used for [Cu2(Indo)4(DMF)2] administration wascrucial to the integrity of the complex.