Endocrine Abstracts

Background: Prednisolone is the most commonly prescribed exogenous glucocorticoid(GC) and its use is frequently associated with the development of iatrogenic Cushing’s Syndrome. Once administered, prednisolone is rapidly converted to inactive prednisone by renal 11β-hydroxysteroid dehydrogenase type 2(11β-HSD2) and subsequently reactivated by 11β-HSD1. We have shown previously that 11β-HSD1 inhibition(with the selective 11β-HSD1 inhibitor, AZD4017) mitigates prednisolone-induced adverse effects¹. Other enzymes, including AKR1C1(20α-hydroxylase), Carbonyl reductase 1(20β-hydroxylase, CBR1) and CYP3A4(6β-hydroxylase) are known to have a role in GC metabolism, but their contributions to prednisolone and prednisone metabolism are entirely unexplored.

Aims: To describe the patterns of unique metabolites(plasma and urine) 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 timed overnight urine collections alongside a detailed 8-h 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. We employed repeated measure ANOVA, Area Under the Curve(AUC) analysis as well as logistic regression.

Results: Urine sample analysis identified 20 discrete prednisolone metabolites. Following oral prednisolone administration (20 mg), timed (0–8 h) plasma metabolite analysis demonstrated that prednisolone (AUC=820±213 ng/ml) and prednisone (AUC=154±50 ng/ml) were the most abundant metabolites, followed by 20β-OH metabolites (AUC_{20β-OH-prednisolone}=69.5±71.2; AUC_{20β-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 (Δ_AUC=−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, at least in part, through increased (+93%, P=0.007) CBR-1 activity assessed by 20β-OH prednisone relative to 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 has a major role to regenerate active exogenous prednisolone. However, preferential prednisone clearance, principally through the activity of CBR1 (but also AKR1C1), further limits the potential for prednisone reactivation and may represent another important mechanism mitigating the adverse effects of prescribed GCs. Finally, 20β-OH-prednisone may emerge as predictor of prednisolone-related adverse effects that may lead to a more precise and personal approach to prednisolone prescribing.

Reference: ¹ 11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial.

Othonos et al., NatComm 2023; doi:10.1038/s41467-023-36541-w.