Involvement of Phenobarbital and SKF 525A in the Hepatotoxicity of Antifungal Drugs Itraconazole and Fluconazole in Rats

Abstract

Itraconazole and fluconazole are potent wide spectrum antifungal drugs. Both of these drugs induce hepatotoxicity clinically. The mechanism underlying the hepatotoxicity is unknown. The purpose of this study was to investigate the role of phenobarbital (PB), an inducer of cytochrome P450 (CYP), and SKF 525A, an inhibitor of CYP, in the mechanism of hepatotoxicity induced by these two drugs in vivo. Rats were pretreated with PB (75 mg/kg for 4 days) prior to itraconazole or fluconazole dosing (20 and 200 mg/kg for 4 days). In the inhibition study, for 4 consecutive days, rats were pretreated with SKF 525A (50 mg/kg) or saline followed by itraconazole or fluconazole (20 and 200 mg/kg) Dose-dependent increases in plasma alanine aminotransferase (ALT), gamma-glutamyl transferase (gamma-GT), and alkaline phosphatase (ALP) activities and in liver weight were detected in rats receiving itraconazole treatment. Interestingly, pretreatment with PB prior to itraconazole reduced the ALT and gamma-GT activities and the liver weight of rats. No changes were observed in rats treated with fluconazole. Pretreatment with SKF 525A induced more severe hepatotoxicity for both itraconazole and fluconazole. CYP 3A activity was inhibited dose-dependently by itraconazole treatment. Itraconazole had no effects on the activity of CYP 1A and 2E. Fluconazole potently inhibited all three isoenzymes of CYP. PB plays a role in hepatoprotection to itraconazole-induced but not fluconazole-induced hepatotoxicity. SKF 525A enhanced the hepatotoxicity of both antifungal drugs in vivo. Therefore, it can be concluded that inhibition of CYP may play a key role in the mechanism of hepatotoxicity induced by itraconazole and fluconazole.

Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole

“…When rats were pretreated with phenobarbital, an inducer of cytochrome P450, hepatotoxicity induced by itraconazole was significantly reduced (27,37). On the other hand, pretreatment of rats with SKF 525A, an inhibitor of cytochrome P450, significantly enhanced itraconazole-induced hepatoxicity (27). These results suggest that inhibition of cytochrome P450, probably CYP3A4, by itraconazole is, at least in part, responsible for itraconazoleinduced hepatotoxicity.…”

“…Itraconazole also inhibits the enzyme activity of CYP3A4 (26). When rats were pretreated with phenobarbital, an inducer of cytochrome P450, hepatotoxicity induced by itraconazole was significantly reduced (27,37). On the other hand, pretreatment of rats with SKF 525A, an inhibitor of cytochrome P450, significantly enhanced itraconazole-induced hepatoxicity (27).…”

“…In addition to lanosterol 14 alpha-demethylase (25), itraconazole is also known to be a potent inhibitor of human liver cytochrome P450 3A4 (CYP3A4), accounting for its extensive drug-drug interactions with other medications (26). It is believed that the effect of itraconazole on CYP3A4 is responsible for the human hepatotoxicity (27). The commercial itraconazole consists of four cis-stereoisomers of itraconazole, including IT-A (2S,4R,2 0 R), IT-B (2R,4S,2 0 R), IT-C (2S,4R,2 0 S), and IT-D (2R,4S,2 0 S).…”

Development of antiproliferative nanohybrid compound with controlled release property using ellagic acid as the active agent

“…Hepatocytes from normal healthy Sprague Dawley rats (n = 4) were isolated by a two-step collagenase perfusion technique. [44][45][46] Viability of freshly isolated rat hepatocytes was determined by trypan blue exclusion. After isolation, hepatocytes suspensions were incubated at a density of 1 × 10 6 viable cells/mL in Leibovitz Glutamax I (L-15 incomplete) medium.…”

Synthesis and Biological Evaluation of Amide Derivatives of (6-Chloro-2,3-dihydro-1H-inden-1-yl)acetic Acid as Potential Anti-inflammatory Agents with Lower Gastrointestinal Toxicity

“…These metabolites may arise via their hydrolytic metabolism to deamidated product. We, therefore, studied the anti-inflammatory activity of compounds 6a and 6p in carrageenan induced rat paw edema model using SKF-525A, a standard hepatic microsomal enzyme inhibitor, 14) pretreated rats. Examination of Table 7 reveals that there is no significant difference between data generated from this test and those generated using standard protocol.…”