Abstract
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 (3) H-cortisone to (3) H-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.