Further Evidence of Extensive Pulmonary First‐pass Ester Hydrolysis after Airways Administration in Rats

The aim of this study was to synthesize an ester with low lipophilicity, and to use this ester to further investigate pre-absorptive pulmonary first-pass metabolism. Hexanoic acid phenethyl ester was synthesized by reacting 2-phenylethanol with hexanoyl chloride. Pre-absorptive first-pass metabolism was assessed by comparing the areas under the blood concentration-time curves after intra-arterial administration of the hexanoic acid phenethyl ester with those after intratracheal instillation. Hexanoic acid phenethyl ester experienced extensive first-pass metabolism (53% of the absorbed dose) before or during absorption. This and earlier data suggests that the extent of this first-pass extraction is dependent on the physicochemical properties of the ester and in particular whether a compound experiences diffusion-limited absorption. Pre-absorptive pulmonary first-pass metabolism of compounds whose absorption is diffusion-rate limited may be extensive even when pulmonary enzyme expression is low. This has consequences for the systemic delivery of drugs and in particular esters via the lungs.