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Abstract for IMM97008

Range-Finding Report on the Immunotoxicity of Itraconazole in Female B6C3F1 Mice

CASRN: 84625-61-6
Chemical Formula: C35H38Cl2N8O4
Molecular Weight: 705.6432
Report Date: July 2006


The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.

Itraconazole, an antifungal agent, is a broad-spectrum triazole derivative that is highly lipophilic and kerotophilic. ICZ has good oral absorption and extensive tissue distribution. The main active metabolite of ICZ is hydroxyitraconazole. For any drug therapy, the risk-benefit consideration is important. In general, the drug is well tolerated with an adverse experience incidence of 9-28% for patients who receive ICZ up to 12 months at 100 mg/day. The most common side effects are gastrointestinal complaints and headache. Since ICZ is usually taken orally by patients with immune depression, it is of great concern how this drug affects the immune responses.

Itraconazole was nominated to the NTP for toxicological evaluation and was selected for immunotoxicity studies by the project officer. Thus, the purpose of these studies was to determine the potential effects of ICZ on the immune system.

The study reported here is an initial range-finding study conducted in female B6C3F1 mice. The animals were treated daily for 28 days by oral gavage. Itraconazole was prepared weekly as a solution in the vehicle 0.2% methylcellulose in 0.1% Tween 80.

In this range-finding study of orally administered ICZ at 10, 20, 40, 80, and 160 mg/kg/day for 28 days, there were no significant effects on body weight. Animals treated with ICZ gained weight at a greater rate than the vehicle animals; however, the increases were not statistically significant due to the variability of the response. Other toxicological parameters, including hematology and organ weights, were not affected with the exception of liver weight, which was increased at the 10 and 80 mg/kg dose levels. The increase in liver weight appeared to be due in part to the increased body weights of the animals in the study.

There were few notable changes among the immunological parameters that were assessed. Evaluation of innate immunity by natural killer cell activity, NK cell numbers, and macrophage cell numbers demonstrated that this component of the immune system was not affected by ICZ treatment. Furthermore, humoral immunity, evaluated by the plaque assay, sheep erythrocytes enzyme-linked immunosorbent assay, and spleen B cell numbers, was also unaffected by treatment with ICZ. Cell-mediated immunity was evaluated by enumeration of splenic T cells and T cell subsets and functionally in the mixed leukocyte response. In all of the cell-mediated parameters, ICZ-treated groups were not significantly different from the vehicle controls.

In conclusion, based on the experimental design of this protocol, ICZ did not affect the immune response in female B6C3F1 mice following 28 days of daily exposure. Accordingly, it is unlikely that the immune system would be a target for ICZ in man. Based on the lack of effects observed in this range-finding study, further evaluation in a full protocol study is not warranted.