Stereoselective pharmacokinetics of stable isotope (+/-)-[ 13C]-pantoprazole: Implications for a rapid screening phenotype test of CYP2C19 activity

David L. Thacker, Anil Modak, Phuong D. Nguyen, David A. Flockhart, Zeruesenay Desta

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Aims: We have previously shown that the (±)-[13C]- pantoprazole breath test is a promising noninvasive probe of CYP2C19 activity. As part of that trial, plasma, breath test indices and CYP2C19 (*2, *3, and *17) genotype were collected. Here, we examined whether [13C]-pantoprazole exhibits enantioselective pharmacokinetics and whether this enantioselectivity is correlated with indices of breath test. Methods: Plasma (-)- and (+)-[13C]-pantoprazole that were measured using a chiral HPLC were compared between CYP2C19 genotypes and correlated with breath test indices. Results: The AUC(0-∞) of (+)-[13C]-pantoprazole in PM (*2/*2, n = 4) was 10.1- and 5.6-fold higher that EM (*1/*1or *17, n = 10) and IM (*1/*2or *3, n = 10) of CYP2C19, respectively (P < 0.001). The AUC(0-∞) of (-)-[13C]-pantoprazole only significantly differed between PMs and EMs (1.98-fold; P = 0.05). The AUC(0-∞) ratio of (+)-/(-)-[13C]- pantoprazole was 3.45, 0.77, and 0.67 in PM, IM, and EM genotypes, respectively. Breath test index, delta over baseline show significant correlation with AUC(0-∞) of (+)-[13C]-pantoprazole (Pearson's r = 0.62; P < 0.001). Conclusions: [13C]-pantoprazole exhibits enantioselective elimination. (+)-[13C]-pantoprazole is more dependent on CYP2C19 metabolic status and may serve as a more attractive probe of CYP2C19 activity than (-)-[13C]-pantoprazole or the racemic mixture.

Original languageEnglish (US)
Pages (from-to)904-909
Number of pages6
JournalChirality
Volume23
Issue number10
DOIs
StatePublished - Nov 2011

Keywords

  • breath test
  • genotype
  • pharmacokinetics
  • racemic

ASJC Scopus subject areas

  • Organic Chemistry
  • Analytical Chemistry
  • Drug Discovery
  • Pharmacology
  • Catalysis
  • Spectroscopy

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