Document Detail

Novel type of ornithine-glutathione double conjugate excreted as a major metabolite into the bile of rats administered clebopride.
MedLine Citation:
PMID:  2359408     Owner:  NLM     Status:  MEDLINE    
Rats orally given radioactive Clebopride [[14C]CP; N-(1'-benzyl-4'-piperidyl)-2-[14C]methoxy-4-amino-5-chlorobenzamide++ +], an antiulcer agent, excreted a novel type of ornithine (Orn)-GSH double conjugate in the bile as a major metabolite [( 14C]BMCP), corresponding to 18% of the dose. The present study provides the first evidence for Orn conjugation of a xenobiotic in mammals and demonstrates that the structure of the radioactive conjugate differs fundamentally from those known in birds and reptiles. The structure of the biliary metabolite, [14C]BMCP, purified to homogeneity by silica gel thin layer and reverse phase high pressure liquid chromatography, was elucidated as S-[2-ornithylamino-4-[14C]methoxy-5-(1'-methyl-4'-piperidylamin o) carboxyphenyl]glutathione, based mainly on the following facts: 1) BMCP showed a protonated molecular ion (M + H)+ peak at m/z 683 in the secondary ion mass spectrum and 2) [14C]BMCP afforded Orn, glutamic acid, glycine, S-(2-amino-4-[14C]methoxy-5-carboxyphenyl)cysteine [( 14C]AMCC), and 1-methyl-4-aminopiperidine (MAP) quantitatively, in an equal molar ratio, by complete hydrolysis with peptidase. Thus, BMCP was a metabolite with three enzymatically hydrolyzable amide bonds in addition to the one existing originally in the parent structure of the drug, which produces MAP by peptic digestion. Of the three additional amide bonds of BMCP, one was a novel type of bond formed by condensation of the alpha-carboxylic acid group of Orn with the primary aromatic amino group of the drug and the other two were in the S-glutathionyl residue, substituted for the chlorine atom vicinal to the Orn-conjugating primary amino group in the aromatic ring and affording glutamic acid, glycine, and the S-cysteine conjugate AMCC by hydrolysis of BMCP with the peptidase. Substitution of a methyl group for the benzyl group at the piperidine ring nitrogen atom, leading to the formation of MAP by peptic digestion, also occurred during metabolism of CP to BMCP.
T Ishizuka; I Komiya; A Hiratsuka; T Watabe
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Molecular pharmacology     Volume:  37     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1990 Jun 
Date Detail:
Created Date:  1990-08-01     Completed Date:  1990-08-01     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  983-9     Citation Subset:  IM    
Toxicology Research Laboratory, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
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MeSH Terms
Benzamides / pharmacology*
Bile / drug effects,  metabolism*
Carbon Radioisotopes
Glutathione / analogs & derivatives*,  metabolism
Metabolic Clearance Rate
Ornithine / analogs & derivatives*,  metabolism
Rats, Inbred Strains
Spectrophotometry, Ultraviolet
Structure-Activity Relationship
Reg. No./Substance:
0/Benzamides; 0/Carbon Radioisotopes; 129596-89-0/S-(2-ornithylamino-4-methoxy-5-(1'-methyl-4'-piperidylamino)carboxyphenyl)glutathione; 55905-53-8/clebopride; 70-18-8/Glutathione; 7006-33-9/Ornithine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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