Drug delivery studies in Caco-2 monolayers. Synthesis, hydrolysis, and transport of O-cyclopropane carboxylic acid ester prodrugs of various beta-blocking agents. Pharmaceutical research. [Pharm Res] Journal article | | Title | Drug delivery studies in Caco-2 monolayers. Synthesis, hydrolysis, and transport of O-cyclopropane carboxylic acid ester prodrugs of various beta-blocking agents. | | Author(s) | Hovgaard L, Brøndsted H, Buur A, Bundgaard H | | Institution | Royal Danish School of Pharmacy, Department of Pharmaceutics, Copenhagen O. | | Source | Pharm Res 1995 Mar; 12(3):387-92. | | MeSH | Acebutolol
Adrenergic beta-Antagonists
Alprenolol
Cells, Cultured
Drug Delivery Systems
Esters
Humans
Hydrolysis
Mathematics
Permeability
Time Factors
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 7617526 |
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