The Potential Role for Corticosterone in the Induction of Cleft Palate in Mice After Treatment With a Selective NK-1 Receptor Antagonist, Casopitant (GW679769B)
Version of Record online: 29 NOV 2011
© 2011 Wiley-Liss, Inc.
Birth Defects Research Part B: Developmental and Reproductive Toxicology
Volume 95, Issue 1, pages 54–62, February 2012
How to Cite
Ziejewski, M. K., Solomon, H. M., Stanislaus, D., Clark, R. L., White, T. E. and Apostoli, A. R. (2012), The Potential Role for Corticosterone in the Induction of Cleft Palate in Mice After Treatment With a Selective NK-1 Receptor Antagonist, Casopitant (GW679769B). Birth Defects Research Part B: Developmental and Reproductive Toxicology, 95: 54–62. doi: 10.1002/bdrb.20341
- Issue online: 16 MAR 2012
- Version of Record online: 29 NOV 2011
- Manuscript Accepted: 22 SEP 2011
- Manuscript Received: 17 AUG 2011
- Substance P;
- cleft palate;
Casopitant is a potent and selective NK-1 receptor antagonist that has shown clinical efficacy in the prevention of chemotherapy-induced and postoperative-induced nausea and vomiting.
In an embryo-fetal development study, pregnant mice were given vehicle (sterile water) or doses of 30, 100, or 300 mg/kg/day casopitant on Gestation Day (GD) 6 to 15. Fetuses were evaluated for external, visceral, and skeletal abnormalities on GD 18. In a follow-on study to investigate casopitant-induced hormonal changes during the developmental period for palate formation, pregnant mice were given vehicle (sterile water) or 300 mg/kg/day casopitant once daily on GD 6 to 13. Blood was collected on GD 13 at various time-points for measurement of plasma adrenocorticotropic hormone and corticosterone (CRT) concentrations.
There was no evidence of developmental toxicity in mice at 30 or 100 mg/kg/day but 9% of fetuses at 300 mg/kg/day had cleft palate. Mice are sensitive to glucocorticoid-induced cleft palates, and NK-1 antagonists are known to modulate the hypothalamic–pituitary–adrenal axis leading to increases in corticosterone. On GD 13, mean plasma adrenocorticotropic hormone levels at 300 mg/kg/day were elevated by approximately twofold from vehicle-treated levels at 1 hr post-dose and mean plasma CRT levels were elevated by 3, 5, and 10-fold at 0.5, 1, and 2 hr post-dose, respectively.
The increased level of CRT was in the range previously shown in the literature to cause cleft palates in mice and was likely the underlying mechanism behind casopitant-induced cleft palate in mice.