Abstract
Background and Purpose: 11β‐Hydroxysteroid dehydrogenase‐1 (11β‐HSD1) catalyses the oxoreduction of cortisone to cortisol, amplifying levels of active glucocorticoids. It is a pharmaceutical target in metabolic disease and cognitive impairments. 11β‐HSD1 also converts some 7oxo‐steroids to their 7β‐hydroxy forms. A recent study in mice described the ratio of tauroursodeoxycholic acid (TUDCA)/tauro‐7oxolithocholic acid (T7oxoLCA) as a biomarker for decreased 11β‐HSD1 activity. The present study evaluates the equivalent bile acid ratio of glycoursodeoxycholic acid (GUDCA)/glyco‐7oxolithocholic acid (G7oxoLCA) as a biomarker for pharmacological 11β‐HSD1 inhibition in humans and compares it with the currently applied urinary (5α‐tetrahydrocortisol + tetrahydrocortisol)/tetrahydrocortisone ((5αTHF + THF)/THE) ratio. Experimental Approach: Bile acid profiles were analysed by ultra‐HPLC tandem‐MS in blood samples from two independent, double‐blind placebo‐controlled clinical studies of the orally administered selective 11β‐HSD1 inhibitor AZD4017. The blood GUDCA/G7oxoLCA ratio was compared with the urinary tetrahydro‐glucocorticoid ratio for ability to detect 11β‐HSD1 inhibition. Key Results: No significant alterations were observed in bile acid profiles following 11β‐HSD1 inhibition by AZD4017, except for an increase of the secondary bile acid G7oxoLCA. The enzyme product/substrate ratio GUDCA/G7oxoLCA was found to be more reliable to detect 11β‐HSD1 inhibition than the absolute G7oxoLCA concentration in both cohorts. Comparison of the blood GUDCA/G7oxoLCA ratio with the urinary (5αTHF + THF)/THE ratio revealed that both successfully detect 11β‐HSD1 inhibition. Conclusions and Implications: 11β‐HSD1 inhibition does not cause major alterations in bile acid homeostasis. The GUDCA/G7oxoLCA ratio represents the first blood biomarker of pharmacological 11β‐HSD1 inhibition and may replace or complement the urinary (5αTHF + THF)/THE ratio biomarker.
| Original language | English |
|---|---|
| Number of pages | 14 |
| Journal | British Journal of Pharmacology |
| Early online date | 23 Sept 2023 |
| DOIs | |
| Publication status | E-pub ahead of print - 23 Sept 2023 |
Bibliographical note
This work was supported by the Swiss National Science Foundation Grants 31003A-179400 and 310030-214978 (A.O.). A.J.S. is funded by a Sir Jules Thorn Award for Biomedical Science. The trials were registered at Clinicaltrials.gov: NCT03111810, Targeting iatrogenic Cushing's Syndrome with 11β-hydroxysteroid dehydrogenase Type 1 inhibition (TICSI), and NCT02017444, Safety and Effectiveness of 11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017) to Treat Idiopathic Intracranial Hypertension (IIH:DT); and European Clinical Trials Database (EudraCT Number: 2013-003643-31). AstraZeneca provided compound AZD4017. The funders of the study and AstraZeneca had no role in the design, conduct of this study, analysis or interpretation of the data. Open access funding provided by Universitat Basel.Keywords
- glucocorticoid
- inhibitor
- LC–MS
- biomarker
- 11β‐hydroxysteroid dehydrogenase
- disease
- bile acid