title: Intestinal first-pass metabolism via carboxylesterase in rat jejunum and ileum.
abstract: 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 microl/min) increased approximately 3-fold compared with control, whereas its degradation clearance (32.5 +/- 5.40 microl/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. V(max) 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.
authors: Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-Honmachi, Kumamoto, Japan.
authors: Kenji
authors: K
authors: Masaki
authors: Mitsuru
authors: M
authors: Hashimoto
authors: Teruko
authors: T
authors: Imai
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism; D000813:Anilides / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects / Q000201:enzymology*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009596:Nitrophenols / Q000378:metabolism / Q000494:pharmacology; D011433:Propranolol / Q000031:analogs & derivatives* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000813:Anilides; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009596:Nitrophenols; D012333:RNA, Messenger; C079647:O-isovaleryl propranolol; C019498:4-nitroaniline; C002887:bis(4-nitrophenyl)phosphate; C001536:1-leucine-4-nitroanilide; C008642:4-nitrophenyl acetate; D011433:Propranolol; D002265:Carboxylic Ester Hydrolases; D000626:Aminopeptidases