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

Abstract

AbstractBackground and Purpose11β‐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 ApproachBile 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 ResultsNo 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 Implications11β‐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.