Carbonyl Reductase 1 regulates prednisolone clearance and modifies its adverse effect profile

OBJECTIVE: Prednisolone is widely prescribed but associated with marked interindividual variability in adverse effects. While 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes regulate glucocorticoid activation, the contribution of alternative clearance pathways remains unclear. We aimed to characterize prednisolone metabolism beyond 11β-HSD enzymes, define the roles of carbonyl reductase 1 (CBR-1) and AKR1C1, and assess the clinical relevance of specific metabolites. DESIGN: Post-hoc targeted metabolomic analysis of a randomized, double-blind, placebo-controlled trial combined with mechanistic in vitro overexpression studies. METHODS: Thirty healthy male volunteers from the TICSI trial (NCT03111810) and HEK293 cells overexpressing CBR-1 or AKR1C1 were studied. Participants received prednisolone (20 mg daily for one week) with placebo or the selective 11β-HSD1 inhibitor AZD4017. In vitro, transfected HEK293 cells were treated with prednisolone or prednisone. Steroid metabolites were quantified by targeted LC-MS/MS, and associations with glucose disposal and osteocalcin were assessed. RESULTS: 20β-reduced metabolites were major contributors to prednisolone clearance. In vitro, CBR-1 preferentially reduced prednisone, with 20β-dihydro-prednisone accounting for up to 78% of its clearance, whereas AKR1C1 had minimal impact. In vivo, 11β-HSD1 inhibition reduced prednisolone exposure without a compensatory rise in prednisone, with a relative increase in CBR-1-mediated 20β-reduction. Higher circulating 20β-dihydro-prednisone at 4 hours independently predicted improved glucose disposal and higher osteocalcin levels. CONCLUSIONS: CBR-1 is a key determinant of prednisolone and prednisone clearance in humans and is associated with clinically relevant metabolic and skeletal outcomes. Circulating 20β-dihydro-prednisone may serve as an informative biomarker of glucocorticoid exposure and adverse effect risk, supporting metabolite-guided approaches to glucocorticoid therapy.