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

Gómez, C, Alimajstorovic, Z, Othonos, N, Winter, DV, White, S, Lavery, GG ORCID: https://orcid.org/0000-0001-5794-748X, Tomlinson, JW, Sinclair, AJ and Odermatt, A, 2024. Identification of a human blood biomarker of pharmacological 11β‐hydroxysteroid dehydrogenase 1 inhibition. British Journal of Pharmacology, 181 (5), pp. 698-711. ISSN 0007-1188

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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.

Item Type:	Journal article
Publication Title:	British Journal of Pharmacology
Creators:	Gómez, C., Alimajstorovic, Z., Othonos, N., Winter, D.V., White, S., Lavery, G.G., Tomlinson, J.W., Sinclair, A.J. and Odermatt, A.
Publisher:	Wiley
Date:	March 2024
Volume:	181
Number:	5
ISSN:	0007-1188
Identifiers:	Number Type 10.1111/bph.16251 DOI 2554468 Other
Rights:	© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	09 Jan 2026 11:42
Last Modified:	09 Jan 2026 11:42
URI:	https://irep.ntu.ac.uk/id/eprint/55005

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