title: Drug delivery studies in Caco-2 monolayers. Synthesis, hydrolysis, and transport of O-cyclopropane carboxylic acid ester prodrugs of various beta-blocking agents.
abstract: A series of O-cyclopropane carboxylic acid ester prodrugs of various beta-blocking agents was synthesized. All prodrugs were hydrolyzed to give their parent compounds in aqueous phosphate buffer of pH 7.4 and in 80% human plasma. The half-lives in buffer solutions varied from 4 hours for the timolol prodrug to about 1 day for the prodrug of alprenolol. In human plasma the half-lives were shorter, ranging from 1 to 7 hours. The formation of the O-cyclopropane carboxylic acid ester derivatives significantly increased the lipophilicities of the beta-blockers as measured by the distribution coefficient between n-octanol and aqueous phosphate buffer of pH 7.4. To characterize the biomembrane permeability characteristics of the beta-blockers, transport properties across Caco-2 cell monolayers were investigated. An increase in lipophilicity resulted in a higher permeability of the prodrugs as compared to the parent compounds. Hence, acebutolol experienced an increment of a factor 17 on the apparent permeability coefficient, Papp, whereas Papp for the more lipophilic drug propranolol was increased by a factor of only 1.26. Some conversion of the prodrugs to their parent compounds was observed during the transport and appeared to be due to enzymatic intracellular metabolism.
authors.affiliation: Royal Danish School of Pharmacy, Department of Pharmaceutics, Copenhagen O.
authors.forename: L
authors.initials: L
authors.lastname: Hovgaard
authors.forename: H
authors.initials: H
authors.lastname: Brøndsted
authors.forename: A
authors.initials: A
authors.lastname: Buur
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
mesh_terms: D000070:Acebutolol / Q000737:chemistry; D000319:Adrenergic beta-Antagonists / Q000737:chemistry*; D000526:Alprenolol / Q000737:chemistry; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004952:Esters / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008433:Mathematics; D010539:Permeability; D013997:Time Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D004952:Esters; D000070:Acebutolol; D000526:Alprenolol