In uteroexposure to itraconazole during different gestational periods of rats

Abstract

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.

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

“…These observations may be supported by the study that was done by El‐Shershaby et al. () who found that fetuses whose mothers were treated during the preimplantation‐implantation period with 100 and 150 mg/kg of itraconazole and through the organogenesis period with 150 mg/kg of itraconazole were resorbed early. Furthermore, Tripathi et al.…”

“…Furthermore, Vogel and Speilmann (1986) added that during the preimplantation period, defects in DNA repair enzymes and low antioxidant enzyme levels lead to high DNA fragmentation and preimplantation embryos may have a lower capacity for DNA repair than adult tissues. These observations may be supported by the study that was done by El-Shershaby et al (2014) who found that fetuses whose mothers were treated during the preimplantation-implantation period with 100 and 150 mg/kg of itraconazole and through the organogenesis period with 150 mg/kg of itraconazole were resorbed early. Furthermore, Tripathi et al (2008) revealed that the fetus and newborn are more susceptible to genetic damage in comparison to the adult, due to an underdeveloped metabolizing enzyme profile and also due to the decrease in the DNA repair capacity in newborn as compared to adult.…”

“…() reported that ROS may play an essential role in DNA damage and apoptosis. Some other authors reported the genotoxicity of some antifungal drugs (Hassan, ; Yüzbaşioğlu et al., ) and of itraconazole (El‐Shershaby et al., ) , however, other authors reported the absence of genotoxicity of other antifungal drugs (Perez‐Rivera et al., ).…”

“…It was reported in several publications that itraconazole had teratogenic effect in mice, rats, and rabbit (Van Cauteren et al, 1989;Tiboni et al, 2006). Moreover, our previous work showed that the effect of itraconazole on fetuses varied according to the time of exposure (El-Shershaby et al, 2014). On the other hand, Cornely et al (2007) reported that hepatotoxic reactions are among the most common and potentially serious adverse effects associated with triazole therapy.…”

“…It was reported in several publications that itraconazole had teratogenic effect in mice, rats, and rabbit (Van Cauteren et al., ; Tiboni et al., ). Moreover, our previous work showed that the effect of itraconazole on fetuses varied according to the time of exposure (El‐Shershaby et al., ). On the other hand, Cornely et al.…”