Biomonitoring of the Genotoxic and Hepatotoxic Effects and Oxidative Stress Potentials of Itraconazole in Pregnant Rats.

BACKGROUND: Pregnant women are more susceptible to both vaginal colonization and infection by yeast. One hundred million fungal infected patients have been treated worldwide with itraconazole (Caputo, 2003. METHOD: Itraconazole was administrated orally to pregnant rats at doses of 75, 100, or 150 mg/kg during gestational days (GD) 1 to 7 or GD 8 to 14 or GD 14 to 20. The genotoxicity and hepatotoxicity of the antifungal drug itraconazole were assessed during different periods of pregnancy using different methods. RESULTS: It was found that itraconazole was a genotoxic drug for both mothers and fetuses. This finding was observed via significant elevation in the estimated comet assay parameters (percentage of fragmented DNA, tail moment, and olive moment), percentage of fragmented DNA measured by diphenylamine assay and mixed smearing and laddering of DNA fragments of liver samples. In addition, itraconazole caused significant elevation in the level of hepatic malondialdehyde and depletion in the catalase activity and glutathione level. Furthermore, itraconazole induced histopathological alterations in the hepatic tissues of both mothers and fetuses. CONCLUSION: These findings indicate that itraconazole administration at doses of 75, 100, or 150 mg/kg during pregnancy induced maternal and fetal toxicity that could be induced by the genotoxicity and the oxidative damage.

In utero exposure to itraconazole during different gestational periods of rats.

The present study aimed to investigate the teratogenic and genotoxic effects of itraconazole administered orally to pregnant rats on gestation days 1-7 (implantation), 8-14 (organogenesis) and 14-20 (fetal developmental period) at doses 75, 100 or 150 mg/kg b.wt. The results indicated that itraconazole had embryolethal effect when administered at a dose of 150 mg/kg b.wt throughout implantation and organogenesis periods as well as at 100 mg/kg b.wt during implantation period. Itraconazole elevated the teratogenicity when administrated at a dose of 100 mg/kg b.wt during organogenesis period, the most prominent abnormalities were abdominal hernia, protruding tongue, exencephaly, incompletely ossified, unossified or missing skull bones (mostly frontal, parietal and interparietal), abnormal vertebrae and fused and supernumerary ribs. However, minimal adverse effects were observed at doses given during the fetal developmental period. Itraconazole increased DNA damage of fetal osteocytes via significant increase in the measured comet parameters in all the treated groups, indicating that itraconazole severely affects fetal genetic material.