Stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor, in extensive and poor metabolizers of S-mephenytoin

Clin Pharmacol Ther. 2001 Mar;69(3):108-13. doi: 10.1067/mcp.2001.113723.

Abstract

Pantoprazole, a proton pump inhibitor, is administered as a racemic mixture. To determine the role of cytochrome P450 (CYP) 2C19 in the stereoselective metabolism of pantoprazole, we investigated the pharmacokinetic disposition of (+)- and (-)-pantoprazole in 7 extensive metabolizers and 7 poor metabolizers of S-mephenytoin. All of the subjects received an oral 40-mg dose of racemic pantoprazole as the enteric-coated formulation. In the extensive metabolizers, the mean clearance of (-)-pantoprazole was only slightly lower than that of (+)-pantoprazole and no significant differences in the other pharmacokinetic parameters between (+)- and (-)-pantoprazole were observed. The mean (+)/(-) ratios for maximum concentration, area under the plasma concentration-time curve from 0 to infinity, and elimination half-life were 0.94, 0.82, and 0.90, respectively. In contrast, in the poor metabolizers, the clearance values of both enantiomers were significantly lower than those in the extensive metabolizers, and a significant difference in pharmacokinetics between (+)- and (-)-pantoprazole was observed. The mean elimination half-life for (+)-pantoprazole was 3.55-fold longer than that of (-)-pantoprazole, and the mean maximum concentration and area under the plasma concentration-time curve from 0 to infinity for (+)-pantoprazole were 1.31- and 3.59-fold greater, respectively, than those for (-)-pantoprazole. These results indicate that the stereoselective metabolism of pantoprazole depends on S-mephenytoin 4'-hydroxylase (CYP2C19). The metabolism of (+)-pantoprazole was impaired to a greater extent than (-)-pantoprazole in the poor metabolizers.

Publication types

  • Clinical Trial

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Administration, Oral
  • Adult
  • Anti-Ulcer Agents / administration & dosage
  • Anti-Ulcer Agents / blood
  • Anti-Ulcer Agents / metabolism
  • Anti-Ulcer Agents / pharmacokinetics*
  • Anticonvulsants / metabolism*
  • Area Under Curve
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / blood
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacokinetics*
  • Chromatography, High Pressure Liquid
  • Half-Life
  • Humans
  • Male
  • Mephenytoin / metabolism*
  • Metabolic Clearance Rate
  • Omeprazole / analogs & derivatives
  • Pantoprazole
  • Stereoisomerism
  • Sulfoxides / administration & dosage
  • Sulfoxides / blood
  • Sulfoxides / metabolism
  • Sulfoxides / pharmacokinetics*

Substances

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Anti-Ulcer Agents
  • Anticonvulsants
  • Benzimidazoles
  • Sulfoxides
  • Pantoprazole
  • Omeprazole
  • Mephenytoin