Evidence for the involvement of a pulmonary first-pass effect via carboxylesterase in the disposition of a propranolol ester derivative after intravenous administration.

The disposition kinetics of O-butyryl propranolol (butyryl-PL), a model compound containing an ester moiety, after intravenous administration was compared with that of PL in rats and beagle dogs. Rats showed only 30% conversion of butyryl-PL to PL up to 2 h after dosing, whereas dogs showed nearly complete conversion within 10 min after administration. The CL(total) of butyryl-PL in rats was 5.8 l/h/kg and that in dogs was 65.6 +/- 18.6 l/h/kg, both of which were greater than hepatic blood flow. The in vivo conversion from butyryl-PL to PL in the rat could be explained on the basis of the hydrolysis characteristics in the liver and blood. The in vitro hydrolysis data and the in vivo data after intra-arterial administration clearly demonstrated that the extremely high CL(total) of butyryl-PL in dogs was dependent on first-pass hydrolysis in the lung in addition to hydrolysis at a blood flow-limited rate in the liver and kidney. The availability of butyryl-PL after passage through the lung was 50%. Furthermore, the isoform of carboxylesterase involved in the pulmonary hydrolysis of butyryl-PL in the dog was identified as D1, a CES-1 group enzyme. However, butyryl-PL was not recognized as a substrate by CES-1 family carboxylesterases, which are present at high levels in the rat lung (RH-1) and kidney (RL-1). These findings indicate that extrahepatic metabolism, especially in the lung, is important in the disposition of drugs containing an ester moiety after intravenous administration and that the substrate specificity of carboxylesterase isozyme distinguishes from others.