KY-556 (N556)

Characteristics of 1,3-bis-(2-ethoxycarbonylchromon-5-yloxy)-2-((S)- lysyloxy)propane dihydrochloride (N-556), a prodrug for the oral delivery of disodium cromoglycate, in absorption and excretion in rats and rabbits

The absorption and excretion of 1,3-bis-(2-ethoxycarbonylchromon-5-yloxy)-2- ((S)-lysyloxy)propane dihydrochloride (N-556), which is a prodrug for the oral delivery of disodium cromoglycate (DSCG), were studied in rats and rabbits. In both animal species, the plasma concentration of DSCG after oral administration of N-556 peaked within 1.0 h, and thereafter declined with a half-life of about 1.2 h in rats and rabbits. The area under the plasma DSCG level versus time curve (AUC) increased in proportion to the dose of N-556 in both animals. The bioavailability of N-556 as calculated from AUC was about 6% in rats and 40% in rabbits, whereas that of DSCG was only 0.1% in rats and 2.5% in rabbits. About 2% and 15% of the dose were respectively excreted as DSCG in the urine and bile after the oral administration of N-556 in rats. The ratio of biliary excretion to urinary excretion (B/U) after the oral administration of N-556 was about twice that after the intravenous injection of DSCG. In rabbits, the urinary and biliary excretions of DSCG after oral administration of N-556 were about 25% and 5%, respectively. The B/U ratio after the oral administration of N-556 in rabbits was similar to that after intravenous administration of DSCG. The difference in the systemic bioavailability of N-556 between rats and rabbits thus appears to be due to a first-pass effect, in addition to a difference in the absorption rate.

Absorption mechanism of 1,3-bis(2-ethoxycarbonylchromon-5-yloxy)-2-((S)-lysyloxy )propane dihydrochloride (N-556), a prodrug for the oral delivery of disodium cromoglycate

To clarify the absorption mechanism of 1,3-bis(2-ethoxycarbonylchromon-5-yloxy)-2-((S)-lysyloxy+ ++)propane dihydrochloride (N-556), a prodrug for the oral delivery of disodium cromoglycate (DSCG), a study was made using rats. N-556 gave the highest plasma level of DSCG following its injection into the loop at the upper part of the small intestine. N-556 was stable in acidic washings of gastric contents, but rapidly hydrolyzed to M1 with twin ethyl residues on DSCG in the washings of the small intestinal contents. N-556 and M1 were hydrolyzed to DSCG via M2 having a mono ethyl residue in the homogenate of the small intestinal mucosa. The oral absorption of M1 following its administration in 50% (v/v) propylene glycol solution was essentially the same as that of N-556. That of M1 administered in aqueous suspension was low. After the oral administration of N-556, a small amount of M2 and a trace of M3 having L-lysyl residue were detected in the portal plasma, but no hydrolytic intermediate except DSCG could be found in the general plasma. The major absorption mechanism of N-556 may thus be concluded as follows: N-556 given orally is transferred to the small intestine in essentially intact form. N-556 is then rapidly diffused to an aqueous layer on the surface of the mucosal membrane and hydrolyzed to M1. The resultant M1 is transported to the mucosal membrane and hydrolyzed to DSCG via M2. DSCG generated in the mucosal membrane is used for general circulation through the portal blood and liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of N-556 on experimental allergy models in rats

The oral anti-allergic effect of 1,3-bis-(2- ethoxycarbonylchromon-5-yloxy)-2-((S)-lysyloxy)propane dihydrochloride (N-556, KY-556) was investigated. 1) N-556 (10-100 mg/kg, p.o.) inhibited dose-dependently the 48-hr homologous PCA in rats, and the duration of action was longer than that of intravenous DSCG. 2) N-556 (20 and 100 mg/kg once a day for 20 consecutive days, p.o.) tended to inhibit the histamine release from actively sensitized rat lung fragments. 3) N-556 (100 mg/kg, p.o.) showed the prolongation of survival time in the rat systemic anaphylaxis. 4) N-556 (100 mg/kg, p.o.) significantly inhibited the increased airway resistance in experimental asthma in rats. These results suggest that N-556 is a promising and orally-active pro-drug of disodium cromoglycate (DSCG) against allergic diseases.

Role of mast cells, eosinophils and IL-5 in the development of airway hyperresponsiveness in sensitized mice

Background and objective: In order to study the role of mast cells and IL-5 in allergen-induced airway hyperreactivity in mice, airway responsiveness in WBB6F1-W/Wv mice (mast cell deficient) and the effects of anti-IL-5 monoclonal antibody (NC-17) and three anti-allergic drugs (N-556, ketotifen and amlexanox) on airway hyperreactivity in Balb/c mice were studied.
Methods: Mice were immunized with an antigen (ovalbumin; OA) at intervals of 12 days. OA was inhaled 10 days after the secondary immunization. Twenty-four hours after the last inhalation, airway reactivity to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was obtained.
Results: Three inhalations of OA caused an increase in leucocytes (including eosinophils), accompanied by increases in IL-5 in BALF, and airway hyperreactivity to acetylcholine in Balb/c and WBB6F1- +/+ mice. In WBB6F1-W/Wv mice, antigen inhalation resulted in increases in leucocytes and IL-5 in BALF but did not result in airway hyperreactivity. NC-17 at doses between 10 and 20 micrograms (intratracheal injection) inhibited the antigen-induced eosinophilia but did not affect airway hyperreactivity in Balb/c mice. Three 'anti-allergic' drugs clearly inhibited antigen-induced increases in IL-5 levels and the number of eosinophils in BALF, but did not affect airway hyperreactivity in Balb/c mice.
Conclusions: These data suggest that mast cells play an important role in the onset of airway hyperreactivity but do not play a role in the production of IL-5 and eosinophilia. Furthermore, indicate that the inhibition of IL-5 is not always associated with a reduction in antigen-induced airway hyperreactivity in mice.