Identification of a human blood biomarker of pharmacological 11β‐hydroxysteroid dehydrogenase 1 inhibition.

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. [ABSTRACT FROM AUTHOR]