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

Cristina Gómez, Zerin Alimajstorovic, Nantia Othonos, Denise V Winter, Sarah White, Gareth G Lavery, Jeremy W Tomlinson, Alexandra J Sinclair, Alex Odermatt

British journal of pharmacology 2024 Mar

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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. 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. 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. 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. © 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Citation

Cristina Gómez, Zerin Alimajstorovic, Nantia Othonos, Denise V Winter, Sarah White, Gareth G Lavery, Jeremy W Tomlinson, Alexandra J Sinclair, Alex Odermatt. Identification of a human blood biomarker of pharmacological 11β-hydroxysteroid dehydrogenase 1 inhibition. British journal of pharmacology. 2024 Mar;181(5):698-711