Involvement of phenobarbital and SKF 525A in the hepatotoxicity of antifungal drugs itraconazole and fluconazole in rats.
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.
Somchit
N
N
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia. nhareet@medic.upm.edu.my
Wong
C W
CW
Zuraini
A
A
Ahmad Bustamam
A
A
Hasiah
A H
AH
Khairi
H M
HM
Sulaiman
M R
MR
Israf
D A
DA
D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D015725:Fluconazole / Q000633:toxicity*; D006993:Hypnotics and Sedatives / Q000633:toxicity*; D007527:Isoenzymes / Q000378:metabolism; D017964:Itraconazole / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009929:Organ Size; D010634:Phenobarbital / Q000633:toxicity*; D011335:Proadifen / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D007527:Isoenzymes; D017964:Itraconazole; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010634:Phenobarbital