title: Continuous inhibition of 11β-hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: P
authors.initials: P
authors.lastname: Morentin Gutierrez
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: A
authors.initials: A
authors.lastname: Gyte
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: J
authors.initials: J
authors.lastname: deSchoolmeester
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: P
authors.initials: P
authors.lastname: Ceuppens
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: J
authors.initials: J
authors.lastname: Swales
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: C
authors.initials: C
authors.lastname: Stacey
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.|Department of Medical Sciences, Uppsala University, 751 85, Uppsala, Sweden.
authors.forename: J W
authors.initials: JW
authors.lastname: Eriksson
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Sjöstrand
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Nilsson
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: B
authors.initials: B
authors.lastname: Leighton
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D001565:Benzoates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004151:Dipeptides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013618:Tachyphylaxis
chemical_list: C000589241:4-(4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl)benzoic acid; D001565:Benzoates; D004151:Dipeptides; D011720:Pyrazoles; C028342:compound 20; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1