ABSORPTION MECHANISM OF XYCARBONYLCHROMON-5-YLOXY)-2-((S)-LYSYLOXY)PROPANE DIHYDROCHLORIDE (N-556), A PRODRUG FOR THE ORAL DELIVERY OF DISODIUM-CROMOGLYCATE

To clarify the absorption mechanism of xycarbonylchromon-5-yloxy)-2-(( S)-lysyloxy)propane dihydrochloride (N-556), a prodrug for the oral de livery of disodium cromoglycate (DSCG), a study was made using rats. N -556 gave the highest plasma level of DSCG following its injection int o the loop at the upper part of the small intestine. N-556 was stable in acidic washings of gastric contents, but rapidly hydrolyzed to Ml w ith twin ethyl residues on DSCG in the washings of the small intestina l contents. N-556 and Ml were hydrolyzed to DSCG via M2 having a mono ethyl residue in the homogenate of the small intestinal mucosa. The or al absorption of M1 following its administration in 50% (v/v) propylen e glycol solution was essentially the same as that of N-556. That of M 1 administered in aqueous suspension was low. After the oral administr ation 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 intermed iate except DSCG could be found in the general plasma. The major absor ption mechanism of N-556 may thus be concluded as follows: N-556 given orally is transferred to the small intestine in essentially intact fo rm. 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 tran sported to the mucosal membrane and hydrolyzed to DSCG via M2. DSCG ge nerated in the mucosal membrane is used for general circulation throug h the portal blood and liver. A small amount of M2 in the mucosal memb rane is transported to the portal blood and hydrolyzed to DSCG in the portal blood and/or liver to make DSCG available for the general circu lation.