Specificity of Esterases and Structures of Prodrug Esters. III. Activity of Rat Tissue Homogenates, Rat Plasma and Porcine Liver Esterase for the Hydrolysis of 3‘,5’-Bis-dicarboxylic Acid Hemiesters of 5-Fluoro-2‘-deoxyuridine

Abstract

Five acidic 3‘,5’-diesters of 5-fluoro-2‘-deoxyuridine (FUdR) including 3-carboxypropionate, 4-carboxybutyrate, 5-carboxypentanoate, 6-carboxyhexanoate and 7-carboxyheptanoate were synthesized, and their susceptibility to porcine liver, rat liver homogenate, rat intestinal homogenate and rat plasma esterase preparations was studied. The susceptibility of the derivatives to porcine liver esterase preparation increased as the number of methylene groups in the ester promoiety increased in both acidic (pH 5.0) and neutral (pH 7.0) solutions. The derivatives showed about 100 times higher reactivity to the esterase at pH 5.0 than at pH 7.0. With the rat tissue homogenates and plasma preparations, the longer the ester chain the higher the susceptibility, except for 3’,5’-bis(3-carboxypropionyl)FUdR (I) with rat liver homogenate. Though the reactivity of I was the lowest with porcine liver esterase preparation and not measurable with rat intestinal homogenate and plasma, I showed the highest reactivity with the rat liver homogenate. © 1985, The Pharmaceutical Society of Japan. All rights reserved.