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In-vivo effects of itraconazole on hepatic mixed-function oxidase
Z Damanhouri1, M Gumbleton, P J Nicholls
1Welsh School of Pharmacy, UWIST, Cardiff, UK.
Abstract:
The effects of itraconazole, a triazole antifungal agent, on cytochrome P450 were investigated by measuring the anti-convulsant activity of phenytoin in mice, and zoxazolamine paralysis time, tolbutamide clearance, and plasma dicoumarol concentrations after a single injection of dicoumarol, in rats. Itraconazole, given either as a single dose of 5 or 10 mg/kg, or daily at these levels for five days, had no significant effect on any of the measures. The drug therefore appears to be free of enzyme inhibiting or inducing activity, although an effect on other cytochrome P450 isozymes can not be discounted. Thus itraconazole may possibly show fewer clinically significant drug interactions at the level of hepatic mixed function oxidase than other azole antifungal agents.
Insights
Itraconazole, a triazole antifungal, did not significantly affect drug metabolism in animal models. This suggests itraconazole may have fewer drug interactions related to liver enzymes compared to other azole antifungals.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Azole antifungal agents are widely used but can cause drug interactions.
- Cytochrome P450 enzymes play a crucial role in drug metabolism.
- Understanding the interaction potential of itraconazole is important for clinical use.
Purpose of the Study:
- To investigate the effects of itraconazole on cytochrome P450 activity.
- To assess the potential for drug interactions with itraconazole.
- To compare itraconazole's interaction profile with other azole antifungals.
Main Methods:
- Animal models (mice and rats) were used to assess drug metabolism.
- Phenytoin anti-convulsant activity was measured in mice.
- Zoxazolamine paralysis time, tolbutamide clearance, and dicoumarol plasma concentrations were measured in rats.
- Itraconazole was administered at single doses of 5 or 10 mg/kg, or daily for five days.
Main Results:
- Itraconazole did not significantly alter phenytoin anti-convulsant activity.
- No significant effects were observed on zoxazolamine paralysis time, tolbutamide clearance, or dicoumarol plasma concentrations.
- Itraconazole demonstrated no significant enzyme-inhibiting or -inducing activity in the tested models.
Conclusions:
- Itraconazole appears to lack significant inhibitory or inducing activity on the specific cytochrome P450 isozymes studied.
- The findings suggest itraconazole may have a lower potential for clinically significant drug interactions via hepatic mixed-function oxidase compared to other azole antifungals.
- Further investigation into other cytochrome P450 isozymes is warranted.