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Lookup NU author(s): Professor Brian WalkerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Authors 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1; EC 1.1.1.146) generates active glucocorticoid hormones. Small molecule inhibitors have been developed to target 11β-HSD1 for the treatment of dementia; these must enter brain subregions, such as the hippocampus, to be effective. We previously reported mass spectrometry imaging measurement of murine tissue steroids, and deuterated steroid tracer infusion quantification of 11β-HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11β-HSD1 inhibitor that accesses the brain. [9,11,12,12-2H]4-Cortisol was infused (1.75 mg/day) by minipump for 2 days into C57Bl6 mice (male, age 12 weeks, n = 3/group) after which an 11β-HSD1 inhibitor (UE2316) was administered (25 mg/kg oral gavage) and animals culled immediately or 1, 2 and 4 h post-dosing. Mice with global genetic disruption of Hsd11B1 were studied similarly. Turnover of d4-cortisol to d3-cortisone (by loss of the 11-deuterium) and regeneration of d3-cortisol (by 11β-HSD1-mediated reduction) were assessed in plasma, liver and brain using matrix assisted laser desorption ionization coupled to Fourier transform cyclotron resonance mass spectrometry. The tracer d4-cortisol was detected in liver and brain following a two day infusion. Turnover to d3-cortisone and on to d3-cortisol was slower in brain than liver. In contrast, d3-cortisol was not detected in mice lacking 11β-HSD1. UE2316 impaired d3-cortisol generation measured in whole body (assessed in plasma; 53.1% suppression in rate of appearance in d3-cortisol), liver and brain. Differential inhibition in brain regions was observed; active glucocorticoids were suppressed to a greater in extent hippocampus or cortex than in amygdala. These data confirm that the contribution of 11β-HSD1 to the tissue glucocorticoid pool, and the consequences of enzyme inhibition on active glucocorticoid concentrations, are substantial, including in the brain. They further demonstrate the value of mass spectrometry imaging in pharmacokinetic and pharmacodynamic studies.
Author(s): Cobice DF, Livingstone DEW, McBride A, MacKay CL, Walker BR, Webster SP, Andrew R
Publication type: Article
Publication status: Published
Journal: Biochemical Pharmacology
Year: 2018
Volume: 148
Pages: 88-99
Print publication date: 01/02/2018
Online publication date: 15/12/2017
Acceptance date: 13/12/2017
Date deposited: 09/01/2018
ISSN (print): 0006-2952
ISSN (electronic): 1873-2968
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.bcp.2017.12.013
DOI: 10.1016/j.bcp.2017.12.013
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