Continuous inhibition of 11[beta]-hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice

Background and Purpose 11[beta]-hydroxysteroid dehydrogenase type I (11[beta]-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 11[beta]-HSD1 activity in human, rat and mouse adipose tissue (AT). Experimental Approach Studies included abdominally obese human volunteers, rats and mice. Two specific 11[beta]-HSD1 inhibitors (AZD8329 and COMPOUND-20) were administered as single oral doses or repeat daily doses for 7-9days. 11[beta]-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 11[beta]-HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11[beta]-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 11[beta]-HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND-20 for 7days. Conclusions and Implications Human and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11[beta]-HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11[beta]-HSD1 inhibitors may be misleading. Investigators of the effects of 11[beta]-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.