Continuous inhibition of 11β‐hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice

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.

Abbreviations

11β‐HSD1

11β‐hydroxysteroid dehydrogenase type I

PK/PD

pharmacokinetic‐pharmacodynamic

AT

adipose tissue

DIO

diet induced obese

IHC

International Conference on Harmonisation

GCP

Good Clinical Practice

b.i.d.

twice daily

u.i.d.

once daily

HPMC

hydroxypropylmethylcellulose

IC₇₀

concentration that delivers 70% of the maximum effect

IC₉₀

concentration that delivers 90% of the maximum effect

fu

fraction unbound

C_max

maximum achieved concentration

C_min

minimum or trough concentration

E₀

baseline

E_max

maximum effect

ANCOVA

analysis of covariance

     

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