RT Journal Article
SR Electronic
T1 Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1089
OP 1095
DO 10.1124/dmd.106.013862
VO 35
IS 7
A1 Kenji Masaki
A1 Mitsuru Hashimoto
A1 Teruko Imai
YR 2007
UL http://dmd.aspetjournals.org/content/35/7/1089.abstract
AB 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 approximately 90% of CES activity without influencing aminopeptidase activity or the transport of l-leucyl-p-nitroanilide and p-nitroaniline, nonester compounds. When isovaleryl-PL was perfused into the jejunal lumen after BNPP treatment, its absorption clearance (7.60 ± 0.74 μl/min) increased approximately 3-fold compared with control, whereas 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 the mucosal S9 fraction. Vmax values for valeryl-PL, isovaleryl-PL, and p-nitrophenyl acetate in the jejunal S9 fraction were 1.7- to 2.5-fold higher than that in the ileal S9 fraction, which agreed with the jejunum/ileum ratio (approximately 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. The American Society for Pharmacology and Experimental Therapeutics