Prednisone reduces ketoconazole-induced skeletal defects in rat fetuses

Abstract

Ketoconazole (KT) is a broad-spectrum antifungal agent whose pharmacological activity is based on the capability to interfere with steroid biosynthesis through an interaction with fungal cytochrome P-450 enzymes and thereby avoiding the formation of fungal walls. As the inhibition of fungal cytochrome P-450 by KT is not specific, the mammalian cytochrome P-450 species, which play an important role in the biosynthesis of steroidogenesis, are also affected. The reproductive and developmental toxicity of KT have been assessed. This antimycotic agent has been reported as embryotoxic and teratogenic when administered in high doses (80 mg/kg) to pregnant rats. The mechanisms by which KT exert teratogenic effects remains to be elucidated. When considering the potential inhibitory effect of KT on mammalian steroid biosynthesis as a possible responsible for the skeletal anomalies induced by this drug, this study aimed at determining whether steroid maternal supplementation may prevent the skeletal anomalies induced by KT. To test this hypothesis, maternal supplementation with prednisone (PRED) (0.1, 0.2 or 0.4 mg/kg) and 80 mg/kg of KT were administered to pregnant Wistar rats (n = 10) during organogenesis period. On gestational day 21, the dams were euthanized and examined for standard parameters of reproductive outcome. In summary, the results showed that PRED supplementation therapy may cause reductions in the incidence of KT-induced cranial and appendicular skeletal anomalies as well as cleft palate in the rat, being these results more consistent with 0.4 mg/kg of this drug. These results suggest an important role for glucocorticoids in KT-induced teratogenesis.

A successful case of Cushing's disease pregnancy treated with ketoconazole

“…In the elegant experiment of Amaral and Nunes [7], prednisone was used in rat mothers for a possible reduction of Ktc teratogenicity effect (skeletal defects) in rat fetuses. Prednisone dose-dependent protection was observed in rat fetuses of these mothers.…”

“…However, it is not recommended for use in pregnancy (Grade C recommendation according to the data of the FDA) [4] because of its teratogenic and embryotoxic consequences, such as skeletal anomalies, when administered in high doses to pregnant rats [4,7] and because of its antiandrogenic effects which in rats can interfere with the development of the external genitalia of male fetuses, decrease anogenital distance and reduce testicular testosterone levels [8]. In this paper we report a case of a patient with CD who became pregnant, under Ktc therapy.…”

Management of Adrenal Tumors in Pregnancy

“…44,48 Although a population-based study of its use showed no negative outcomes, 49 hepatic dysfunction is possible and there have been reports of teratogenic effect in rats. 50 Both metyrapone and ketoconazole are pregnancy risk category C, indicating that a risk to the fetus cannot be ruled out. Mitotane, an adrenolytic, is a US Food and Drug Administration (FDA) category D pregnancy risk.…”

Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period – comparison with vitamin A‐induced malformation spectrum

“…However, since these mechanisms have yet to be clearly determined, human risk assessment has not been sufficiently performed. Ketoconazole (KCZ) is an imidazole antifungal drug used for oral treatment of topical and systemic mycoses, and is known to produce fetal malformation in rodents (Nishikawa et al ., ; Tachibana et al ., ; Buttar et al ., ; Amaral and Nunes, ; Taxvig et al ., ). However, little has been reported regarding the fetal malformation spectrum when KCZ is administered to pregnant rats by single gavage during organogenesis.…”