Effects of Cytochrome P450 Inhibitors on Itraconazole and Fluconazole Induced Cytotoxicity in Hepatocytes.pdfVIP

Hindawi Publishing Corporation Journal of Toxicology Volume 2009, Article ID 912320, 7 pages doi:10.1155/2009/912320 Research Article Effects of Cytochrome P450 Inhibitors on Itraconazole and Fluconazole Induced Cytotoxicity in Hepatocytes Nhareet Somchit,1 Chong Sock Ngee,1 Azhar Yaakob,1 Zuraini Ahmad,1 and Zainul Amiruddin Zakaria2 1 Pharmacology and Toxicology Unit, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Putra Malaysia (UPM), Serdang, 43400 Selangor, Malaysia 2 Faculty of Pharmacy, MARA University of Technology, 40500 Shah Alam, Malaysia Correspondence should be addressed to Nhareet Somchit, nhareet@.my Received 10 November 2008; Accepted 16 May 2009 Recommended by Peter O’Brien Itraconazole and fluconazole have been reported to induce hepatotoxicity in patients. The present study was designed to investigate the role of cytochrome P450 inhibitors, SKF 525A, and curcumin pretreatment on the cytotoxicity of antifungal drugs fluconazole and itraconazole. For 3 consecutive days, female rats were administered daily SKF 525A or curcumin (5 and 25 mg/kg). Control rats received an equivalent amount of dosed vehicle. The animals were anaesthetized 24 hours after receiving the last dose for liver perfusion. Hepatocytes were then exposed to various concentrations of antifungal drugs. In vitro incubation of hepatocytes with itraconazole revealed significantly lower viability when compared to fluconazole as assessed by lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase activities. The cytotoxicity of itraconazole was enhanced when incubated with hepatocytes pretreated with SKF 525A. SKF 525A had no effects on the cytotoxicity of fluconazole. Curcumin failed to either increase or decrease the