3-hydroxyanthranilic acid accumulation following administration of the 3-hydroxyanthranilic acid 3,4-dioxygenase inhibitor NCR-631

In the kynurenine pathway of tryptophan metabolism, 3-hydroxyanthranilic ac id is the substrate for formation of the excitotoxin quinolinic acid by 3-h ydroxyanthranilic acid 3,4-dioxygenase. This study was designed to characte rize the effects on 3-hydroxyanthranilic acid after treatment with the 3-hy droxyanthranilic acid 3,4-dioxygenase inhibitor 4,6-di-bromo-3-hydroxyanthr anilic acid (NCR-631) in Sprague-Dawley rats. The blood plasma and brain co ncentrations of 3-hydroxyanthranilic acid were found to increase rapidly in a dose-dependent manner after gavage administration of NCR-631. However, t he effect was relatively transient, with a decline in 3-hydroxyanthranilic acid levels already at Ih after NCR-631 treatment. Similar increases in pla sma levels of 3-hydroxyanthranilic acid were observed following either gava ge or parenteral (i.v. or s.c.) administration of NCR-631 (25 mg/kg). Only a minor enhancement of the NCR-631-induced increase in plasma 3-hydroxyanth ranilic acid levels was found after sub-chronic treatment (25 mg/kg by gava ge; 7 days, b.i.d.), suggesting a low propensity for altered 3-hydroxyanthr anilic acid 3,4-dioxygenase activity following repeated inhibition. Adminis tration of [C-14]NCR-631 suggested 20 min initial plasma half life and an o ral absorption around 50%. A dose of 250 mg/kg [C-14]NCR-631 given by gavag e provided plasma levels of almost 2 mu mol/ml and a brain concentration of approximately 16 nmol/g, when analyzed 15 min after administration. Neithe r acute nor sub-chronic administration of NCR-631 caused any substantial ef fects 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 m ajor cerebral tryptophan metabolites 5-hydroxytryptamine and 5-hydroxyindol eacetic acid remained unchanged following administration of NCR-631. Althou gh reversible inhibition of 3-hydroxyanthranilic acid 3,4-dioxygenase with NCR-631 in normal rats is insufficient to cause substantial changes in the levels of quinolinic acid or other important tryptophan metabolites, it cau ses a major accumulation of the substrate 3-hydroxyanthranilic acid. (C) 19 99 Elsevier Science B.V. All rights reserved.