ArticlePharmacology research & perspectives2016
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.
Article in Pharmacology research & perspectives, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 10 citations in OpenAlex.
- Treatment of γ-Hydroxybutyrate (GHB) Overdose with the GABAThe Journal of pharmacology and experimental therapeutics · 2022Article
- Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies.Journal of inherited metabolic disease · 2018Review
- Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells: Therapeutic implications for SSADH deficiency, a GABA metabolic disorder.Toxicology in vitro : an international journal published in association with BIBRA · 2018Article
- Pharmacological sensitivity of reflexive and nonreflexive outcomes as a correlate of the sensory and affective responses to visceral pain in mice.Scientific reports · 2017Article
- In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells.PloS one · 2017Article
- Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency.JIMD reports · 2017Article
- 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 · 2016Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
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
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