Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats

✍ Scribed by Noriko Masubuchi; Hideki Yamazaki; Makoto Tanaka

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 190 KB
• Volume: 10
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/(sici)1520-636x(1998)10:8<747::aid-chir5>3.0.co;2-b

✦ Synopsis

±)-Pantoprazole ((±)-PAN), (±)-5-(difluoromethoxy)-2-[[(3.4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole) is a chiral sulfoxide that is used clinically as a racemic mixture. The disposition kinetics of (+)-PAN and (-)-PAN given separately has been studied in rats. Serum levels of (+)-and (-)-PAN and its metabolites, pantoprazole sulfone (PAN-SO 2 ), pantoprazole sulfide (PAN-S), 4Ј-O-demethyl pantoprazole sulfone (DMPAN-SO 2 ), and 4Ј-O-demethyl pantoprazole sulfide (DMPAN-S) were measured by HPLC. Following single intravenous or oral administration, both enantiomers were rapidly absorbed and metabolized, resulting in similar serum concentrations, suggesting that the two enantiomers have approximately the same disposition kinetics. The major metabolite of both (+)-and (-)-PAN was PAN-SO 2 , while DMPAN-SO 2 was also detected as a minor metabolite. Serum levels of PAN-S and DMPAN-S could not be quantified after intravenous or oral administration of either enantiomer.

Significant chiral inversion occurred after intravenous and oral administration of (+)-PAN. The AUCs of (-)-PAN after intravenous and oral dosing of (+)-PAN were 36.3 and 28.1%, respectively of those of total [(+) + (-)] PAN. In contrast, the serum levels of (+)-PAN were below quantitation limits after intravenous or oral administration of (-)-PAN. Therefore, chiral inversion was observed only after administration of (+)-PAN, supporting the hypothesis that stereoselective inversion from (+)-PAN to (-)-PAN occurs in rats.