Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2024) 104 P37 | DOI: 10.1530/endoabs.104.P37

SFEIES24 Poster Presentations Adrenal & Cardiovascular (40 abstracts)

11β-hydroxysteroid dehydrogenase type 1 inhibition unmasks multiple pathways that may mitigate the adverse effects of prescribed prednisolone

Riccardo Pofi 1 , Sergi Coll 2 , Nantia Othonos 1 , Hamish Miller 1,3 , Tom Potter 1,4 , K. Jane Escott 5 , Andrew Whittaker 6 , Núria Monfort 2,7 , Rosa Ventura 2 & Jeremy W. Tomlinson 1


1Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, United Kingdom; 2Doping Control Research Group, Catalonian Antidoping Laboratory IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 3Barts Liver Centre, Blizard Institute, QMUL, London, United Kingdom; 4Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom; 5Business Development & Licensing, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom; 6Former employee, Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom; 7Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain


Background: Prednisolone is the most prescribed exogenous glucocorticoid (GC) and its use is frequently associated with iatrogenic Cushing’s Syndrome. Once administered, prednisolone is converted to inactive prednisone by renal 11β-hydroxysteroid dehydrogenase type 2(11β-HSD2) and reactivated by 11β-HSD1. We have shown previously that 11β-HSD1 inhibition (with the selective 11β-HSD1 inhibitor, AZD4017) mitigates prednisolone-induced adverse effects. The role of other enzymes, including Carbonyl reductase 1 (20β-hydroxylase, CBR1) in prednisolone and prednisone metabolism are unexplored.

Aims: To describe the patterns of unique plasma metabolites associated with prednisolone and prednisone clearance, define the impact of 11β-HSD1 inhibition and assess correlations between plasma metabolites and clinically significant outcomes.

Methodology: Retrospective analysis of detailed 8-hour assessment period of 2-hourly plasma samples after administering prednisolone (20 mg) with either placebo or AZD4017. Plasma metabolites were quantified using LC-MS/MS. Specific enzyme activity was inferred using the ratio of target metabolite/substrate levels.

Results: Following oral prednisolone administration (20 mg), prednisolone (AUC=820±213 ng/mL) and prednisone (AUC=154±50 ng/mL) were the most abundant metabolites, followed by 20β-OH metabolites (AUC20β-OH-prednisolone= 69.5±71.2; AUC20β-OH-prednisone= 24.8±16.8 ng/mL). Inhibition of 11β-HSD1 activity with AZD4017 decreased prednisolone availability by 59% (p < 0.001). Interestingly, AZD4017 did not increase prednisone availability (ΔAUC= -38.67, 95%CI -84.42;7.08, p = 0.113). Furthermore, 8h after prednisolone administration, prednisone levels were lower in the AZD4017 treated group (Δ-14.88 ng/mL, 95%CI -18.94;-10.83, P < 0.001). This observation was driven through increased (+93%, p = 0.007) CBR-1 activity assessed by 20β-OH prednisone/prednisone concentrations. Logistic regression identified 20β-OH-prednisone(4h) as the only predictor of higher glucose disposal (B=0.382, p = 0.017) and osteocalcin levels (B=0.727, p = 0.006) after prednisolone, indicative of less significant adverse effects.

Conclusions: 11β-HSD1 significantly regenerate active prednisolone. Preferential prednisone clearance by CBR1 limits reactivation, mitigating adverse effects of prescribed GCs. Finally, 20β-OH-prednisone may predict prednisolone-related adverse effects, suggesting a more precise prescribing approach.

Volume 104

Joint Irish-UK Endocrine Meeting 2024

Belfast, Northern Ireland
14 Oct 2024 - 15 Oct 2024

Society for Endocrinology 

Browse other volumes

Article tools

My recent searches

No recent searches.