Phosphorsäur e-bis-[p-nitro-phenylester], ein neuer Hemmstoff mikrosomaler Carboxylesterasen

Heymann, Eberhard; Krisch, K

doi:10.1515/bchm2.1967.348.1.609

Cited by 107 publications

(45 citation statements)

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“…Recently, Quinney et al (2005) reported that loperamide, an opioid compound, competitively inhibited CES, especially human CES2 isozyme, hCE2, with a K i of 1.5 M. However, the effect of loperamide on the activity of other hydrolases is not mentioned in detail, and reduction of gastrointestinal motility by loperamide might affect drug absorption in other ways (Callreus et al, 1999). On the other hand, BNPP is well known as a potent and specific inhibitor of CES isozymes (Heymann and Krisch, 1967;Block and Arndt, 1978;Mentlein et al, 1988). We first determined that BNPP noncompetitively inhibited PNPA hydrolysis in the rat jejunal S9 with a K i value of 44.9 Ϯ 4.95 nM.…”

Section: Discussionmentioning

confidence: 99%

“…BNPP specifically combines with CES and suppresses hydrolase activity by noncompetitive inhibition without any modulation of ␣-chymotrypsin, trypsin, acetylcholinesterase, or nonspecific serum cholinesterase (Heymann and Krisch, 1967;Block and Arndt, 1978;Mentlein et al, 1988). In addition, we investigated the hydrolyzing capacity and expression level of rat intestinal CES isozymes in the jejunum and the ileum.…”

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confidence: 99%

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Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Masaki¹,

Hashimoto²,

Imai³

2007

Drug Metab Dispos

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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 l/min) increased approximately 3-fold compared with control, whereas its degradation clearance (32.5 ؎ 5.40 l/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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Masaki¹,

Hashimoto²,

Imai³

2007

Drug Metab Dispos

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“…In erythrocytes, the CES inhibitor BNPP (10 M) inhibited MMF hydrolysis by only 5.6% relative to control values, whereas the arylesterase inhibitor 5,5Ј-dithiobis(2-nitrobenzoic acid) showed no inhibition at all (Heymann and Krisch, 1967;Costello and Green, 1983) (supplemental data). Therefore, an erythrocyte esterase other than CES and arylesterase, namely acetylcholinesterase, seemed to be responsible for MMF hydrolysis in whole blood.…”

Section: Kinetic Parameters Of Mmf Hydrolysis In S9 From Cos-1 Cells mentioning

confidence: 96%

Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Fujiyama¹,

Miura²,

Kato³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Mycophenolate mofetil (MMF) is the ester prodrug of the immunosuppressant agent mycophenolic acid (MPA) and is rapidly activated by esterases after oral administration. However, the role of isoenzymes in MMF hydrolysis remains unclear. Although human plasma, erythrocytes, and whole blood contain MMF hydrolytic activities, the mean half-lives of MMF in vitro were 15.1, 1.58, and 3.20 h, respectively. Thus, blood esterases seemed to contribute little to the rapid MMF disappearance in vivo. In vitro analyses showed that human intestinal microsomes exposed to 5

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“…ited by DFP and PMSF, inhibitors of serine hydrolases such as carboxylesterase and cholinesterase (Table 3). This activity was also effectively suppressed by BNPP, a selective inhibitor of carboxylesterase, 11) whereas the hydrolysis was not inhibited by physostigmine, a cholinesterase inhibitor.…”

Section: Methylaa In Guinea Pig Liver Microsomes Using Chemical Inhibmentioning

confidence: 98%

Hepatic Metabolism of Methyl Anthranilate and Methyl N-Methylanthranilate as Food Flavoring Agents in Relation to Allergenicity in the Guinea Pig

Yamaori

Yokozuka

Sasama

et al. 2005

JOURNAL OF HEALTH SCIENCE

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Phosphorsäur e-bis-[p-nitro-phenylester], ein neuer Hemmstoff mikrosomaler Carboxylesterasen

Cited by 107 publications

References 0 publications

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Hepatic Metabolism of Methyl Anthranilate and Methyl N-Methylanthranilate as Food Flavoring Agents in Relation to Allergenicity in the Guinea Pig

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