Study On The Metabolism And Stereoselective Pharmacokinetics Of Pantoprazole

Pantoprazole, a chiral benzimidazole sulfoxide derivative, is an irreversible proton pump inhibitor which is used clinically as racemate in the treatment of reflux esophagitis, Zollinger-Ellison syndrome, peptic ulcers, and other acid-related, hypersecretory gastrointestinal disorders. In previous studies on the metabolism and pharmacokinetics of pantoprazole, it is extensively metabolized in the liver through the cytochrome P450 system and also exhibits polymorphic metabolism in humans. Pantoprazole undergoes metabolic pathways including sulfoxide oxidation and reduction (catalyzed mainly by CYP3A4), O-demethylation and aromatic hydroxylation (catalyzed by CYP2C19 and CYP3A4). The demethylated and hydroxylated metabolites then undergo phase II metabolism (glucuronidation or sulfation). In the EMs, the AUC of /-pantoprazole was slightly higher than that of d-pantoprazole. However, significant differences in the AUC (approximately 3 times greater for the d-pantoprazole than that for the /-pantoprazole) were observed in the PMs. It is important for complete understanding of the absorption, distribution, metabolism, and excretion of pantoprazole enantiomers, and for development of pantoprazole enantiomer, to gain further understanding of pantoprazole metabolism and stereoselective pharmacokinetics and its mechanism.The thesis aimed to isolate and identify metabolites of pantoprazole, to investigate pantoprazole metabolism in microbial model and in mammals. The stereoselective pharmacokinetics of pantoprazole was studied by assays for simultaneous determination of pantoprazole and its metabolites in different biological matrices and its mechanism was also revealed. It would offer some references and inspirations for the development of chiral drugs.1. Isolation and identification of pantoprazole metabolitesA total of fifteen metabolites of pantoprazole were isolated from the biotransformed culture sample of pantoprazole by Cunninghamella blakesleeana AS 3.153 and urine sample of rat after multi-dose oral administration of pantoprazole and identified by...