Influence of sub-chronic selective 11β-hydroxysteroid dehydrogenase 1 inhibition on the hypothalamic-pituitary-adrenal axis in female cynomolgus monkeys

• Published in: European journal of pharmacology Vol. 789; pp. 68 - 74
• Main Authors: Hamilton, Bradford S., Schoelch, Corinna, Schuler-Metz, Annette, Krosky, Paula, Lala, Deepak S., Claremon, David A., McGeehan, Gerard M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.10.2016
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11β-hydroxysteroid dehydrogenase 1; Adipose tissue; Animals; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Female; HPA; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - physiology; Inhibitor; Liver; Macaca fascicularis; Oxazines - pharmacokinetics; Oxazines - pharmacology; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - physiology; Pyridones - pharmacokinetics; Pyridones - pharmacology; Time Factors; 11β-hydroxysteroid dehydrogenase 1; HPA; Inhibitor; Adipose tissue; Liver
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.07.004

Inhibition of local cortisol regeneration from circulating cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. Chronic modulation of glucocorticoid homeostasis may result in hypothalamic-pituitary-adrenal (HPA) axis stimulation. HPA axis over-activation leading androgen excess would be undesirable in a therapeutic intervention designed to treat a chronic condition such as the metabolic syndrome. To address whether 11β-HSD1 inhibition would lead to excess androgens, we treated female cynomolgus monkeys with a selective inhibitor, BI 135558, for 4 weeks. Continual action of the compound over the dosing period was confirmed by constant plasma exposure, and a maintained change in urinary glucocorticoid metabolites consistent with 11β-HSD1 inhibition. No significant changes in adrenal function, as evidenced by an adrenocorticotropic hormone (ATCH) challenge, were observed. An examination of androgenic hormones revealed a slight increase in dehydroepiandrosterone sulfate (DHEA-S), while other hormones such as testosterone remained within reference values. Overall, treatment with BI 135558 in monkeys did not result in obvious over-activation of the HPA axis.