Received for publication November 14, 2006.
Revised March 22, 2007.
Accepted for publication March 27, 2007.

Intestinal first-pass metabolism via carboxylesterase in rat jejunum and ileum

Abstract

In order to determine the activity of a major intestinal esterase in the first-pass hydrolysis of O -isovaleryl-propranolol (isovaleryl-PL), a model ester-compound, rat intestinal jejunum and blood vessels were perfused simultaneously after inhibition of a carboxylesterase (CES) by bis-p-nitrophenyl phosphate (BNPP). BNPP specifically inhibits about 90% of CES activity without influencing aminopeptidase activity or the transport of L-leu-p-nitroanilide and p-nitroaniline, non-ester compounds. When isovaleryl-PL was perfused into the jejunal lumen after BNPP treatment, its absorption clearance (7.60 ± 0.74 µL/min) increased about three-fold compared with control, while its degradation clearance (32.5 ± 5.40 µL/min) decreased to 23% of control. Therefore, CES seems to be mainly responsible for the intestinal first-pass hydrolysis of isovaleryl-PL. This finding is consistent with the results from studies of in vitro BNPP inhibition in mucosal S9 fraction. V_max values for valeryl-PL, isovaleryl-PL and p-nitrophenyl acetate in the jejunal S9 fraction were 1.7-2.5 fold higher than that in the ileal S9 fraction, which agreed with the jejunum/ileum ratio (about 1.5-fold) of mRNA expression levels for the CES2 isozymes, AB010635 and AY034877. These findings indicated that CESs expressed in the intestine markedly contribute to first-pass hydrolysis in both jejunum and ileum.

Key words: absorption, carboxylesterases, enzyme kinetics, extrahepatic drug metabolism, first-pass metabolism, inhibition, intestinal bioavailability, prodrugs