KY-109, a new bifunctional prodrug of cephalosporin. II. Mechanism of oral absorption.

Abstract

(5-Methyl-2-oxo-1, 3-doxol-4-yl)methyl (6R, 7R)-7-[(R)-2-[(S)-alanyloxy]-2-phenylacet-amido]-3-[(5-methyl-1, 3, 4-thiadiazol-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate hydrochloride (KY-109) is a bifunctional prodrug designed to improve the oral absorption of the parent drug (KY-087), which is a cephalosporin with a broad spectrum of antibacterial activity.The mechanism of oral absorption of KY-109 was investigated in rats. An aqueous solution of KY-087 and a suspension of KY-106, which is esterified with a (5-methyl-2-oxo-1, 3-dioxol)methyl group at the C-4 carboxy group of KY-087, were poorly absorbed orally in rats. However, a 50% propylene glycol solution of KY-106 and an aqueous solution of KY-109 were well absorbed. KY-109 was rapidly hydrolyzed to KY-106 in the small intestinal contents, though it was hardly hydrolyzed in the stomach contents. FUrther, KY-109 was hydrolyzed to KY-087 via KY-106 in the gastrointestinal homogenate.From these results, the mechanism of the oral absorption of KY-109 can be speculated to be as follows. KY-109 is transferred into the small intestinal lumen without hydrolysis in the stomach, and is then hydrolyzed to KY-106 with the release of the alanyl residue. The resulting KY-106 is then transferred into the mucosal membrane, and hydrolyzed enzymatically with the formation of KY-087 along with acetoin. The resulting KY-087 is then transferred into the blood stream.