A metabolic route of omeprazole involving conjugation with glutathione identified in the rat.
A metabolic route of omeprazole involving glutathione has been established through identification of endproducts excreted in the urine of rats after oral administration of 400 mumol/kg of a mixture of [3H]- and [14C]omeprazole. The labeled positions enabled facile tracing of metabolites that were formed through fission of omeprazole, producing [3H]pyridine and [14C]benzimidazole metabolites. The structures of the metabolites were established by HPLC thermospray MS and MS/MS. Two of the metabolites were isolated and characterized by 1H NMR studies. The fact that the N-acetylcysteine derivative of the benzimidazole was one of the endproducts indicated that the initial reaction involved glutathione. Three metabolites reflecting the fate of the pyridine moiety were identified. Their proposed formation route is via initial reduction to the pyridylmethylthiol compound followed by S-methylation and S-oxidation to the corresponding sulfoxide or sulfone. The quantity of metabolites formed via the glutathione route identified in urine was about 10% of the dose given, both in male and female rats. The male and female rats excreted the same cleaved metabolites and approximately equal quantities thereof.
Weidolf
L
L
Preclinical Research, Astra Hässle AB, Mölndal, Sweden.
Karlsson
K E
KE
Nilsson
I
I
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008297:Male; D009853:Omeprazole / Q000145:classification / Q000652:urine*; D051381:Rats; D011919:Rats, Inbred Strains
D005978:Glutathione; D009853:Omeprazole