SAT302 Circulating And Urinary Metabolites Associated With Total Exposure Of Cortisol And Cortisol Time Profile

Abstract Disclosure: J. McQueen: None. T. Garner: None. D. Chantzichristos: None. O. Ragnarsson: None. R. Bergthorsdottir: None. S. Skrtic: None. A. Stevens: None. G. Johannsson: None. The detrimental effects of excess cortisol exposure are well known, but the disruption of the circadian rhythm itself has also been associated with cardiometabolic and mental disorders. The aim of this study was to better understand these outcomes by identifying metabolites associated with total exposure of cortisol and cortisol time profile separately. This was a hypothesis-generating study using a randomized, two-armed, 12-week cross-over study comparing once-daily (OD) dual-release hydrocortisone tablet treatment with the same daily dose of thrice-daily (TID) conventional immediate-release hydrocortisone tablet treatment. Eighteen patients with primary adrenal insufficiency, who performed a full 24h in-house pharmacokinetic (PK) serum cortisol and urinary free cortisol (UFC) profiling, were included. The total exposure of cortisol was calculated by the area under the curve (AUC) of the observed cortisol concentration over 24h. To describe the variability of the cortisol time profile, the lag-1 autocorrelation (AUTO) of the cortisol concentration was calculated. Metabolites in serum and urine were analyzed using gas and liquid chromatography-mass spectrometry (GC-MS, LC-MS). Analyses were performed in negative and positive mode, and with targeted and untargeted approach. The relationship between AUC, AUTO and expression of metabolites was assessed using a Bayesian generalized linear model. The total exposure of cortisol was 20% higher during TID treatment. The AUTO was lower, reflecting a larger variability during TID compared to OD. In both serum and urine, a total of 775 metabolites were significantly associated with AUC and 479 with AUTO; 206 metabolites were overlapping and thus associated with both total exposure and the time profile. Serum GC-MS identified 55 metabolites correlated with AUC and 24 with AUTO. Among them, 12 metabolites were uniquely correlated with AUTO. Pathway analysis of these metabolites showed a high impact on the taurine and hypotaurine metabolism, and the primary bile acid biosynthesis. Pathway analysis on metabolites uniquely correlated with AUTO, identified in serum using LC-MS, also showed an impact on the primary bile acid biosynthesis, as well as the cysteine and methionine metabolism. Urinary metabolomics identified 21 metabolites correlated with AUC and 2 with AUTO. Pathway analysis of the metabolites in urine uniquely correlated with AUC, showed an impact on the ascorbate and aldarate metabolism, as well as the synthesis and degradation of ketone bodies. Our study identified circulating and urinary metabolites uniquely correlated with total exposure of cortisol and cortisol time profile, respectively. The study results therefore support that the total exposure and the time profile of cortisol may have different metabolic effects. The outcome of the study may be a step towards identifying novel biomarkers of the action of cortisol. Presentation: Saturday, June 17, 2023