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

doi:10.1111/bph.16251

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

Br J Pharmacol. 2024 Mar;181(5):698-711. doi: 10.1111/bph.16251. Epub 2023 Oct 19.

Authors

Cristina Gómez¹, Zerin Alimajstorovic², Nantia Othonos³, Denise V Winter¹, Sarah White³, Gareth G Lavery⁴, Jeremy W Tomlinson³, Alexandra J Sinclair^{2

5}, Alex Odermatt¹

Affiliations

¹ Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
² Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
³ Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
⁴ Department for Biosciences, Nottingham Trent University, Nottingham, UK.
⁵ Department of Neurology, University Hospitals Birmingham, Birmingham, UK.

PMID: 37740611
DOI: 10.1111/bph.16251

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.

Trial registration: ClinicalTrials.gov NCT03111810 NCT02017444.

Keywords: 11β-hydroxysteroid dehydrogenase; LC-MS; bile acid; biomarker; disease; glucocorticoid; inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1*
Animals
Bile Acids and Salts
Biomarkers
Glucocorticoids* / metabolism
Humans
Hydrocortisone / metabolism
Mice
Tetrahydrocortisol

Substances

11-beta-Hydroxysteroid Dehydrogenase Type 1
Bile Acids and Salts
Biomarkers
Glucocorticoids
Hydrocortisone
Tetrahydrocortisol

Associated data

ClinicalTrials.gov/NCT03111810
ClinicalTrials.gov/NCT02017444
EudraCT/2013-003643-31

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding