Quantification of 11b-Hydroxysteroid Dehydrogenase 1 Kinetics and Pharmacodynamic Effects of Inhibitors in Brain using Mass Spectrometry Imaging and Stable-Isotope Tracers in Mice.

Quantification of 11b-Hydroxysteroid Dehydrogenase 1 Kinetics and Pharmacodynamic Effects of Inhibitors in Brain using Mass Spectrometry Imaging and Stable-Isotope Tracers in Mice. Biochem Pharmacol. 2017 Dec 14;: Authors: Cobice DF, Livingstone DEW, McBride A, MacKay CL, Walker BR, Webster SP, Andrew R Abstract 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 11 β -HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11 β -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 hours 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 11 β -HSD1-mediated reduction) was assessed in plasma, liver and brain using matrix assisted laser ...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research