Article date: October 2015
By: P Morentin Gutierrez, A Gyte, J deSchoolmeester, P Ceuppens, J Swales, C Stacey, J W Eriksson, M Sjöstrand, C Nilsson, B Leighton, in Volume 172, Issue 20, pages 4806-4816
Background and Purpose
11β‐hydroxysteroid dehydrogenase type I (11β‐HSD1), a target for Type 2 diabetes mellitus, converts inactive glucocorticoids into bioactive forms, increasing tissue concentrations. We have compared the pharmacokinetic‐pharmacodynamic (PK/PD) relationship of target inhibition after acute and repeat administration of inhibitors of 11β‐HSD1 activity in human, rat and mouse adipose tissue (AT).
Experimental Approach
Studies included abdominally obese human volunteers, rats and mice. Two specific 11β‐HSD1 inhibitors (AZD8329 and COMPOUND‐20) were administered as single oral doses or repeat daily doses for 7–9 days. 11β‐HSD1 activity in AT was measured ex vivo by conversion of 3H‐cortisone to 3H‐cortisol.
Key Results
In human and rat AT, inhibition of 11β‐HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11β‐HSD1 activity after repeat dosing with COMPOUND‐20 with continuous drug cover, but effects were substantially reduced if a ‘drug holiday’ period was maintained daily. Inhibition of 11β‐HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND‐20 for 7 days.
Conclusions and Implications
Human and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11β‐HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11β‐HSD1 inhibitors may be misleading. Investigators of the effects of 11β‐HSD1 inhibitors should confirm that desired levels of enzyme inhibition in AT can be maintained over time after repeat dosing and not rely on results following a single dose.
DOI: 10.1111/bph.13251
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