title: 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.
abstract: 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.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshimi
authors.forename: H
authors.initials: H
authors.lastname: Hashizume
authors.forename: M
authors.initials: M
authors.lastname: Kitagawa
authors.forename: K
authors.initials: K
authors.lastname: Nishimura
authors.forename: N
authors.initials: N
authors.lastname: Kakeya
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D002867:Chromones / Q000097:blood / Q000493:pharmacokinetics*; D004205:Cromolyn Sodium / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002867:Chromones; D011355:Prodrugs; C069179:N 556; D004205:Cromolyn Sodium