title: Stereoselective pharmacokinetics of stable isotope (+/-)-[13C]-pantoprazole: Implications for a rapid screening phenotype test of CYP2C19 activity.
abstract: OBJECTIVE
  We have previously shown that the (±)-[(13) C]-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 [(13) C]-pantoprazole exhibits enantioselective pharmacokinetics and whether this enantioselectivity is correlated with indices of breath test.
  
  
  METHODS
  Plasma (-)- and (+)-[(13) C]-pantoprazole that were measured using a chiral HPLC were compared between CYP2C19 genotypes and correlated with breath test indices.
  
  
  RESULTS
  The AUC( 0-∞) of (+)-[(13) C]-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 (-)-[(13) C]-pantoprazole only significantly differed between PMs and EMs (1.98-fold; P = 0.05). The AUC( 0-∞) ratio of (+)-/(-)-[(13) C]-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 (+)-[(13) C]-pantoprazole (Pearson's r = 0.62; P < 0.001).
  
  
  CONCLUSIONS
  [(13) C]-pantoprazole exhibits enantioselective elimination. (+)-[(13) C]-pantoprazole is more dependent on CYP2C19 metabolic status and may serve as a more attractive probe of CYP2C19 activity than (-)-[(13) C]-pantoprazole or the racemic mixture.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, Indianapolis, Indiana.
authors.forename: David L
authors.initials: DL
authors.lastname: Thacker
authors.forename: Anil
authors.initials: A
authors.lastname: Modak
authors.forename: Phuong D
authors.initials: PD
authors.lastname: Nguyen
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D001944:Breath Tests; D002247:Carbon Isotopes / Q000737:chemistry; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism*; D057075:Enzyme Assays / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077402:Pantoprazole; D010641:Phenotype; D013237:Stereoisomerism; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D002247:Carbon Isotopes; D000077402:Pantoprazole; D065731:Cytochrome P-450 CYP2C19