Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384

D A Katz; W Liu; C Locke; P Jacobson; D M Barnes; R Basu; G An; M J Rieser; D Daszkowski; F Groves; G Heneghan; A Shah; H Gevorkyan; S S Jhee; L Ereshefsky; G J Marek

doi:10.1038/tp.2013.67

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Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384

Journal article

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Peer reviewed

Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384

D A Katz, W Liu, C Locke, P Jacobson, D M Barnes, R Basu, G An, M J Rieser, D Daszkowski, F Groves, …

Translational psychiatry, Vol.3(8), pp.e295-e295

08/27/2013

DOI: 10.1038/tp.2013.67

PMCID: PMC3756293

PMID: 23982627

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Abstract

ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

Adamantane - pharmacology

Central Nervous System - metabolism

Hydrocortisone - cerebrospinal fluid

Hydrogen

Humans

Middle Aged

Hydrocortisone - metabolism

Male

11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors

Piperazines - pharmacology

Dose-Response Relationship, Drug

Central Nervous System - drug effects

Adult

Hydrocortisone - blood

Isotopes

Adamantane - analogs & derivatives

Details

Title: Subtitle: Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384
Creators: D A Katz - AbbVie, North Chicago, IL, USA. david.a.katz@me.com
W Liu
C Locke
P Jacobson
D M Barnes
R Basu
G An
M J Rieser
D Daszkowski
F Groves
G Heneghan
A Shah
H Gevorkyan
S S Jhee
L Ereshefsky
G J Marek
Resource Type: Journal article
Publication Details: Translational psychiatry, Vol.3(8), pp.e295-e295
DOI: 10.1038/tp.2013.67
PMID: 23982627
PMCID: PMC3756293
NLM abbreviation: Transl Psychiatry
ISSN: 2158-3188
eISSN: 2158-3188
Publisher: United States
Language: English
Date published: 08/27/2013
Academic Unit: Epidemiology; Pharmaceutical Sciences and Experimental Therapeutics; General Internal Medicine; Internal Medicine
Record Identifier: 9984065310702771

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