Journal article
A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS‐382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication
Pharmacology research & perspectives, Vol.4(6), pp.e00265-n/a
12/2016
Handle:
https://hdl.handle.net/2376/116621
PMCID: PMC5115179
PMID: 27891231
Abstract
Gamma‐aminobutyric acid (
GABA
) is an endogenous inhibitory neurotransmitter and precursor of gamma‐hydroxybutyric acid (
GHB
).
NCS
‐382 (6,7,8,9‐tetrahydro‐5‐hydroxy‐5H‐benzo‐cyclohept‐6‐ylideneacetic acid), a known
GHB
receptor antagonist, has shown significant efficacy in a murine model of succinic semialdehyde dehydrogenase deficiency (
SSADHD
), a heritable neurological disorder featuring chronic elevation of
GHB
that blocks the final step of
GABA
degradation.
NCS
‐382 exposures and elimination pathways remain unknown; therefore, the goal of the present work was to obtain in vivo pharmacokinetic data in a murine model and to identify the
NCS
‐382 metabolites formed by mouse and human.
NCS
‐382 single‐dose mouse pharmacokinetics were established following an intraperitoneal injection (100, 300, and 500 mg/kg body weight) and metabolite identification was conducted using
HPLC
‐
MS
/
MS
. Kinetic enzyme assays employed mouse and human liver microsomes. Upon gaining an understanding of the
NCS
‐382 clearance mechanisms, a chemical inhibitor was used to increase
NCS
‐382 brain exposure in a pharmacokinetic/pharmacodynamic study. Two major metabolic pathways of
NCS
‐382 were identified as dehydrogenation and glucuronidation. The
K
m
for the dehydrogenation pathway was determined in mouse (
K
m
= 29.5 ± 10.0
μ
mol/L) and human (
K
m
= 12.7 ± 4.8
μ
mol/L) liver microsomes. Comparable parameters for glucuronidation were >100
μ
mol/L in both species. Inhibition of
NCS
‐382 glucuronidation, in vivo, by diclofenac resulted in increased
NCS
‐382 brain concentrations and protective effects in gamma‐butyrolactone‐treated mice. These initial evaluations of
NCS
‐382 pharmacokinetics and metabolism inform the development of
NCS
‐382 as a potential therapy for conditions of
GHB
elevation (including acute intoxication &
SSADHD
).
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Details
- Title
- A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS‐382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication
- Creators
- Garrett R Ainslie - College of PharmacyK. Michael Gibson - College of PharmacyKara R Vogel - College of Pharmacy
- Publication Details
- Pharmacology research & perspectives, Vol.4(6), pp.e00265-n/a
- Academic Unit
- Pharmacotherapy, Department of
- Publisher
- John Wiley and Sons Inc; Hoboken
- Grant note
- SSADH Association R41 NS 98856 / National Institute of Neurological Disorders and Stroke
- Identifiers
- 99900548059401842
- Language
- English
- Resource Type
- Journal article