title: Is (+)-[13C]-pantoprazole better than (±)-[13C]-pantoprazole for the breath test to evaluate CYP2C19 enzyme activity?
abstract: 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.
authors.affiliation: Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Thacker
authors.forename: Anil
authors.initials: A
authors.lastname: Modak
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D001944:Breath Tests; D002245:Carbon Dioxide / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D045853:Exhalation; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077402:Pantoprazole; D013055:Spectrophotometry, Infrared; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D015415:Biomarkers; D004791:Enzyme Inhibitors; D002245:Carbon Dioxide; D000077402:Pantoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19