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An In‐vitro and In‐vivo Correlative Approach to the Evaluation of Ester Prodrugs to Improve Oral Delivery of Propranolol

Abstract— A series of ester prodrugs of propranolol was synthesized by incorporating substituents (straight alkyl, branched alkyl, acyloxyalkyl and cycloalkyl) into the β‐hydroxy function of propranolol with the aim of protecting the drug against first‐pass metabolism following oral administration. The in‐vitro hydrolysis rates of the prodrugs were, in increasing order, liver homogenate ≫ plasma > buffers. The pH‐rate profile of the prodrugs showed maximum stability around pH 4·0; the hydrolysis rates were drastically increased over pH 6·8. QSAR analysis revealed hydrophobic (π) and electronic (σ) effects of the substituents play the main roles for prodrug hydrolysis in buffers and plasma, while hydrolysis in liver homogenate could not be well explained by any of these parameters. Four prodrugs (O‐acetyl‐, O‐butyryl‐, O‐isovaleryl‐ and O‐cyclopropanoyl‐propranolol) were selected for oral administration based on their hydrolysis in‐vitro. Following oral administration of prodrugs to beagle dogs the absolute bioavailabilities (F) of propranolol were about 2–4‐fold that after an equivalent dose of propranolol. The prodrugs were rapidly absorbed and regenerated propranolol to attain peak plasma levels at 0–0·5 h. Intact prodrug levels were also observed, which varied depending on their respective stabilities in in‐vitro media. A linear relationship between F of propranolol and log P was obtained. F further appeared to be parabolically dependent on the observed hydrolysis rates of prodrugs in liver homogenate suggesting optimal design manipulation. The overall in‐vitro and in‐vivo results showed that lipophilic prodrugs having higher chemical and enzymatic stability in buffers and plasma, but susceptible to hydrolysis in the liver homogenate, to be the most promising prodrugs for improving oral bioavailability of propranolol.