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Titolo:
3-hydroxyanthranilic acid accumulation following administration of the 3-hydroxyanthranilic acid 3,4-dioxygenase inhibitor NCR-631
Autore:
Fornstedt-Wallin, B; Lundstrom, J; Fredriksson, G; Schwarcz, R; Luthman, J;
Indirizzi:
Astra Arcus, Preclin R&D, Dept Cell Biol, S-15185 Sodertalje, Sweden AstraArcus Sodertalje Sweden S-15185 l Biol, S-15185 Sodertalje, Sweden Astra Arcus, Preclin R&D, Drug Metab & Pharmacokinet, S-15185 Sodertalje, Sweden Astra Arcus Sodertalje Sweden S-15185 okinet, S-15185 Sodertalje, Sweden Astra Arcus, Pharm R&D, Bioanal, S-15185 Sodertalje, Sweden Astra Arcus Sodertalje Sweden S-15185 ioanal, S-15185 Sodertalje, Sweden Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USAUniv Maryland Baltimore MD USA 21228 iat Res Ctr, Baltimore, MD 21228 USA
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACOLOGY
fascicolo: 1, volume: 386, anno: 1999,
pagine: 15 - 24
SICI:
0014-2999(199912)386:1<15:3AAFAO>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-BRAIN TISSUE; QUINOLINIC ACID; CEREBROSPINAL-FLUID; OXYGENASE ACTIVITY; KYNURENIC ACID; RAT; 4-CHLORO-3-HYDROXYANTHRANILATE; METABOLISM; 6-CHLOROTRYPTOPHAN; NEUROTOXICITY;
Keywords:
kynurenine; 3-hydroxyanthranilic acid; inhibitor; (rat); plasma; brain;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Luthman, J Astra Arcus, Preclin R&D, Dept Cell Biol, S-15185 Sodertalje, Sweden Astra Arcus Sodertalje Sweden S-15185 5185 Sodertalje, Sweden
Citazione:
B. Fornstedt-Wallin et al., "3-hydroxyanthranilic acid accumulation following administration of the 3-hydroxyanthranilic acid 3,4-dioxygenase inhibitor NCR-631", EUR J PHARM, 386(1), 1999, pp. 15-24

Abstract

In the kynurenine pathway of tryptophan metabolism, 3-hydroxyanthranilic acid is the substrate for formation of the excitotoxin quinolinic acid by 3-hydroxyanthranilic acid 3,4-dioxygenase. This study was designed to characterize the effects on 3-hydroxyanthranilic acid after treatment with the 3-hydroxyanthranilic acid 3,4-dioxygenase inhibitor 4,6-di-bromo-3-hydroxyanthranilic acid (NCR-631) in Sprague-Dawley rats. The blood plasma and brain concentrations of 3-hydroxyanthranilic acid were found to increase rapidly in a dose-dependent manner after gavage administration of NCR-631. However, the effect was relatively transient, with a decline in 3-hydroxyanthranilicacid levels already at Ih after NCR-631 treatment. Similar increases in plasma levels of 3-hydroxyanthranilic acid were observed following either gavage or parenteral (i.v. or s.c.) administration of NCR-631 (25 mg/kg). Onlya minor enhancement of the NCR-631-induced increase in plasma 3-hydroxyanthranilic acid levels was found after sub-chronic treatment (25 mg/kg by gavage; 7 days, b.i.d.), suggesting a low propensity for altered 3-hydroxyanthranilic acid 3,4-dioxygenase activity following repeated inhibition. Administration of [C-14]NCR-631 suggested 20 min initial plasma half life and an oral absorption around 50%. A dose of 250 mg/kg [C-14]NCR-631 given by gavage provided plasma levels of almost 2 mu mol/ml and a brain concentration of approximately 16 nmol/g, when analyzed 15 min after administration. Neither acute nor sub-chronic administration of NCR-631 caused any substantial effects on quinolinic acid levels in plasma or brain. Also, the plasma levels of kynurenic acid, another neuroactive kynurenine pathway metabolite, were unaffected by acute NCR-631 treatment. Moreover, the brain levels of the major cerebral tryptophan metabolites 5-hydroxytryptamine and 5-hydroxyindoleacetic acid remained unchanged following administration of NCR-631. Although reversible inhibition of 3-hydroxyanthranilic acid 3,4-dioxygenase withNCR-631 in normal rats is insufficient to cause substantial changes in thelevels of quinolinic acid or other important tryptophan metabolites, it causes a major accumulation of the substrate 3-hydroxyanthranilic acid. (C) 1999 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 12:56:57