Dataset Information

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

ABSTRACT: 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.Plasma (-)- and (+)-[(13) C]-pantoprazole that were measured using a chiral HPLC were compared between CYP2C19 genotypes and correlated with breath test indices.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).[(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.

SUBMITTER: Thacker DL

PROVIDER: S-EPMC4409653 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Thacker David L DL Modak Anil A Nguyen Phuong D PD Flockhart David A DA Desta Zeruesenay Z

Chirality 20110920 10

<h4>Aims</h4>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.<h4>Methods</h4>Plasma (-)- and (+)-[(13) C]-pantoprazole that were measured using a c ...[more]

PMID: 21935988

Similar Datasets

Project description:Recently, we have shown that the (+)-[(13)C]-pantoprazole is more dependent on CYP2C19 metabolic status than (-)-[(13)C]-pantoprazole. In this study, we tested the hypothesis that (+)-[(13)C]-pantoprazole is a more sensitive and selective probe for evaluating CYP2C19 enzyme activity than the racemic mixture. (+)-[(13)C]-pantoprazole (95 mg) was administered orally in a sodium bicarbonate solution to healthy volunteers. Breath and plasma samples were collected before and up to 720 min after dosing. The (13)CO2 in exhaled breath samples was measured by infrared spectrometry. Ratios of (13)CO2/(12)CO2 after (+)-[(13)C]-pantoprazole relative to (13)CO2/(12)CO2 at baseline were expressed as delta over baseline (DOB). (+)-[(13)C]-pantoprazole concentrations were measured by HPLC. Genomic DNA extracted from whole blood was genotyped for CYP2C19*2, *3 and *17 using Taqman assays. Statistically significant differences in the area under the plasma concentration time curve (AUCplasma(0-?) (p < 0.001) and oral clearance (<0.01) of (+)-[(13)C]-pantoprazole as well as in the breath test indices (delta over baseline, DOB30; and area under the DOB versus time curve, AUCDOB(0-120)) (p < 0.01) were observed among poor, intermediate and extensive metabolizer of CYP2C19. DOB30 and AUCDOB(0-120) adequately distinguished poor metabolizer from intermediate and extensive metabolizer of CYP2C19. Breath test indices significantly correlated with plasma elimination parameters of (+)-[(13)C]-pantoprazole (Pearson correlations: -0.68 to -0.73). Although relatively higher breath test indices were observed after administration of (+)-[(13)C]-pantoprazole (this study) than after (±)-[(13)C]-pantoprazole (previous study), the performance of the racemic and the enantiomer as marker of CYP2C19 activity remained similar. Our data confirm that the metabolism of (+)-[(13)C]-pantoprazole is highly dependent on CYP2C19 metabolic status, but the breath test derived from it is not superior to the racemic [(13)C]-pantoprazole in evaluating CYP2C19 activity in vivo. Thus, racemic [(13)C]-pantoprazole which is relatively easy to synthesize and more stable than (+)-[(13)C]-pantoprazole is adequate as a probe of this enzyme.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets