Pharmacokinetics and disposition of a novel NMDA glycine site antagonist (UK-240,455) in rats, dogs and man
| Autor: | D. K. Walker, J. I. Gedge, W. Wild, Susan Cole, Rob Webster, S. J. Roffey |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Adult
Central Nervous System Male medicine.medical_specialty Cell Membrane Permeability N-Methylaspartate Adolescent Health Toxicology and Mutagenesis Glycine Glucuronidation Urine Pharmacology Toxicology Receptors N-Methyl-D-Aspartate Biochemistry Rats Sprague-Dawley Dogs Pharmacokinetics Quinoxalines Internal medicine medicine Carnivora Animals Bile Humans Tissue Distribution Binding Sites biology Chemistry Fissipedia Antagonist Blood Proteins General Medicine Middle Aged biology.organism_classification Rats Endocrinology NMDA receptor Caco-2 Cells |
| Zdroj: | Xenobiotica. 33:541-560 |
| ISSN: | 1366-5928 0049-8254 |
| DOI: | 10.1080/0049825031000085988 |
| Popis: | 1. UK-240,455 ((+) 6,7-dichloro-5-[N-(2-hydroxyethyl)methanesulphonamido]-2,3 (1H,4H)-quinoxalinedione) is a potent, selective N-methyl D-aspartate (NMDA) glycine site antagonist that is being evaluated for the potential treatment of stroke. 2. UK-240,455 is predominately excreted unchanged in urine (58-68%) in rats, dogs and man following intravenous administration. The remainder of the dose is excreted unchanged in the faeces. It is considered that UK-240,455 is predominantly cleared by active renal tubular secretion and active hepatobiliary transport. In man, there is evidence that UK-240,455 undergoes glucuronidation. However, there is no evidence for this in rats and dogs. 3. UK-240,455 has a short elimination half-life in rats, dogs and man (0.4-1.4 h) and clearances of 12, 13 and 6 ml min(-1) kg(-1), respectively. The compound shows limited tissue distribution with volumes of distribution of 0.4-0.8 l kg(-1) in rats, dogs and man. The species' variation in pharmacokinetic parameters was related allometrically when plasma protein binding was taken in to account. Hence, active hepatic or renal clearance processes for this compound were conserved across species. 4. Cerebrospinal fluid and brain concentrations of UK-240,455 were determined in rats. The cerebrospinal fluid/plasma concentration ratio of UK-240,455 was 4.3%, which was similar to the plasma-free fraction of this compound (3%), indicating good blood-brain barrier permeability. Brain tissue concentrations were low (0.7% of the total plasma concentrations). |
| Databáze: | OpenAIRE |
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