Premium
Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period – comparison with vitamin A‐induced malformation spectrum
Author(s) -
Mineshima Hiroshi,
Fukuta Tetsuya,
Kato Emiko,
Uchida Keiji,
Aoki Toyohiko,
Matsuno Yoshiharu,
Mori Chisato
Publication year - 2012
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1636
Subject(s) - ketoconazole , teratology , medicine , toxicity , fetus , endocrinology , physiology , pregnancy , biology , genetics , antifungal , dermatology
Azole derivatives have teratogenic effects in rodents. In the present study, malformations and their sensitive windows induced by high‐dose ketoconazole (KCZ), an azole derivative, without maternal toxicity were investigated. In addition, the malformation spectrum determined was compared with that induced by vitamin A palmitate (VAP). Pregnant rats were administered a single dose of KCZ by oral gavage on specific individual days from gestational days 8 to 15 (GDs 8–15). Maternal animals were subjected to necropsy on GD 20, and the obtained fetuses were examined for external, visceral and skeletal malformations. The malformation spectrum of VAP was identified from available published data (Noda, Sato, and Udaka, 1982) and a complementary study (single administration of VAP at 1 200 000 IU kg −1 ). Embryonic lethality was observed in dams given KCZ on GDs 9–12 with peak incidence on GDs 10 and 11 with complete resorption. KCZ induced major malformations included cleft palate, digital anomalies, misshapen limbs and unique discontinuous ribs, and the sensitive window for each was identified. Compared with the malformations induced by VAP, unique malformations (e.g. discontinuous ribs by KCZ, neural tube defects by VAP), similar malformations with similar sensitive windows (e.g. digital and limb malformations) and similar malformations with different sensitive windows (e.g. embryonic lethality and cleft palate) were distinguished, suggesting that the mechanisms of several of the types of KCZ‐induced malformation are related to excessive vitamin A. Copyright © 2011 John Wiley & Sons, Ltd.