Search: id:"swepub:oai:DiVA.org:uu-267677" >
Continuous inhibiti...
Continuous inhibition of 11 beta-hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice
-
- Gutierrez, P. Morentin (author)
- AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England.
-
- Gyte, A. (author)
- AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England.
-
- deSchoolmeester, J. (author)
- AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England.
-
show more...
-
- Ceuppens, P. (author)
- AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England.
-
- Swales, J. (author)
- AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England.
-
- Stacey, C. (author)
- AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England.
-
- Eriksson, Jan W. (author)
- Uppsala universitet,Klinisk diabetologi och metabolism,AstraZeneca R&D, Molndal, Sweden.
-
- Sjostrand, M. (author)
- AstraZeneca R&D, Molndal, Sweden.
-
- Nilsson, C. (author)
- AstraZeneca R&D, Molndal, Sweden.
-
- Leighton, B. (author)
- AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England.
-
show less...
-
AstraZeneca R&D, Mereside, Macclesfield SK10 4TG, Cheshire, England Klinisk diabetologi och metabolism (creator_code:org_t)
- 2015-10-08
- 2015
- English.
-
In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 172:20, s. 4806-4816
- Related links:
-
https://bpspubs.onli...
-
show more...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- Background and Purpose11-hydroxysteroid dehydrogenase type I (11-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-HSD1 activity in human, rat and mouse adipose tissue (AT). Experimental ApproachStudies included abdominally obese human volunteers, rats and mice. Two specific 11-HSD1 inhibitors (AZD8329 and COMPOUND-20) were administered as single oral doses or repeat daily doses for 7-9days. 11-HSD1 activity in AT was measured ex vivo by conversion of H-3-cortisone to H-3-cortisol. Key ResultsIn human and rat AT, inhibition of 11-HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11-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-HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND-20 for 7days. Conclusions and ImplicationsHuman and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11-HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11-HSD1 inhibitors may be misleading. Investigators of the effects of 11-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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Gutierrez, P. Mo ...
-
Gyte, A.
-
deSchoolmeester, ...
-
Ceuppens, P.
-
Swales, J.
-
Stacey, C.
-
show more...
-
Eriksson, Jan W.
-
Sjostrand, M.
-
Nilsson, C.
-
Leighton, B.
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Pharmacology and ...
- Articles in the publication
-
British Journal ...
- By the university
-
Uppsala University