DRUG-DELIVERY STUDIES IN CACO-2 MONOLAYERS - SYNTHESIS, HYDROLYSIS, AND TRANSPORT OF O-CYCLOPROPANE CARBOXYLIC-ACID ESTER PRODRUGS OF VARIOUS BETA-BLOCKING-AGENTS

A series of O-cyclopropane carboxylic acid ester prodrugs of various b eta-blocking agents was synthesized. All prodrugs were hydrolyzed to g ive their parent compounds in aqueous phosphate buffer of pH 7.4 and i n 80% human plasma. The half-lives in buffer solutions varied from 4 h ours for the timolol prodrug to about 1 day for the prodrug of alpreno lol. In human plasma the half-lives were shorter, ranging from 1 to 7 hours. The formation of the O-cyclopropane carboxylic acid ester deriv atives significantly increased the lipophilicities of the beta-blocker s as measured by the distribution coefficient between n-octanol and aq ueous phosphate buffer of pH 7.4. To characterize the biomembrane perm eability characteristics of the beta-blockers, transport properties ac ross Caco-2 cell monolayers were investigated. An increase in lipophil icity resulted in a higher perme ability of the prodrugs as compared t o the parent compounds. Hence, acebutolol experienced an increment of a factor 17 on the apparent permeability coefficient, Papp, whereas Pa pp for the more lipophilic drug propranolol was increased by a factor of only 1.26. Some conversion of the prodrugs to their parent compound s was observed during the transport and appeared to be due to enzymati c intracellular metabolism.