Received for publication October 4, 2005.
Revised November 22, 2005.
Accepted for publication November 22, 2005.

First-pass hydrolysis of a propranolol ester derivative in rat small intestine

Abstract

In order to evaluate the first-pass hydrolysis of O-isovaleryl-propranolol (isovaleryl-PL), which was used as a model ester-compound, rat intestinal jejunum and blood vessels were perfused simultaneously. The membrane permeability of isovaleryl-PL was greater than PL because it was more lipophilic. Isovaleryl-PL was almost completely hydrolyzed to PL and isovaleric acid (IVA) in epithelial cells at a rate limited by its uptake. Based on pH-partitioning PL and IVA were transported into both vascular (pH 7.4) and luminal sides (pH 6.5). Therefore, when isovaleryl-PL was perfused into the jejunal lumen, more than 90% permeated into the blood vessel as PL. In addition, PL appeared in the lumen at a rate 6-fold greater than in blood vessels. When isovaleryl-PL was perfused its disappearance (50.5 ± 1.95 nmol/min) was the sum of the absorption and secretion rates of PL. In contrast, isovaleric acid (IVA) was transported into blood vessels rather than the jejunal lumen. In addition, the calculated degradation clearance from in vitro hydrolysis (K_m: 13.7 ± 1.71 µM, V_max: 29.1 ± 3.81 nmol/min/mg protein) was 3.42 mL/min/10 cm jejunum, which was 24-fold greater than the observed CL_deg (0.14 ± 0.02 mL/min/10 cm jejunum). These findings indicate that in addition to the liver, the intestine markedly contributes to first-pass hydrolysis.

Key words: absorption, carboxylesterases, extrahepatic drug metabolism, first-pass metabolism, intestinal bioavailability, permeability, pharmacokinetics, prodrugs

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