Abstract
We tested the hypothesis that the stable isotope [13C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the 13CO2 produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles were administered a single oral dose of [13C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled 13CO2 and 12CO2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13CO2/12CO2 after [13C]pantoprazole relative to 13CO2/12CO2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB15 to DOB120, and area under the DOB versus time curve (AUC0–120 and AUC0–∞) were significantly different among three genotype groups (CYP2C19*1/*1, n = 10; CYP2C19*1/*2 or CYP2C19*1/*3, n = 10; and CYP2C19*2/*2, n = 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p < 0.01); linear regression analysis indicated a gene-dose effect relationship (r2 ranged between 0.236 and 0.522; all p < 0.05). These breath test indices were significantly lower in PMs than IMs (p < 0.05) or EMs (p < 0.01) of CYP2C19. [13C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r = -0.74; p = 0.038). These feasibility data suggest that the [13C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grants T32GM008425, 1R01GM078501-01A1]; Otsuka Pharmaceuticals Company [Grant-in-aid; Tokyo, Japan]; and the National Institutes of Health National Center for Research Resources [Grant MO1-RR000750].
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Z.D., A.M., Y.K., and D.A.F. are co-owners of a patent on a clinical test designed to determine CYP2C19 activity using the [13C]pantoprazole breath test (http://www.wipo.int/pctdb/en/wo.jsp?WO=2008028116&IA=US2007077362&DISPLAY=STATUS).
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D.A.F. has served as a paid consultant for Roche Molecular Diagnostics (Indianapolis, IN). The other authors declare no conflict of interest.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.147751.
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ABBREVIATIONS: PM, poor metabolizer; IM, intermediate metabolizer; EM, extensive metabolizer; UM, ultrarapid metabolizer; GCRC, General Clinical Research Center; DOB, delta over baseline; PDR, percentage dose recovered; DOBmax, maximal DOB; Tmax, time to maximal concentration or DOB; AUC, area under the concentration-time curve or area under DOB-time curve; Cmax, maximal plasma concentration.
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↵1 Current affiliation: Otsuka Pharmaceuticals, Princeton, New Jersey.
- Received October 22, 2008.
- Accepted January 8, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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