Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [ 13C]pantoprazole breath test

Zeruesenay Desta, Anil Modak, Phuong D. Nguyen, Suzanne M. Lemler, Yasuhisa Kurogi, Lang Li, David A. Flockhart

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

We tested the hypothesis that the stable isotope [ 13C]panto- prazole is O-demethylated by cytochrome P450 CYP2C19 and that the 13CO 2 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]pantopra-zole sodium-sesquihydrate ( 00 mg) with 2. g of sodium bicarbonate. Exhaled 13CO 2 and 12CO 2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13CO 2/ 12CO 2 after [ 13C]pantoprazole relative to 13CO 2/ 12CO 2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB 15 to DOB 120, and area under the DOB versus time curve (AUC 0-120, and AUC 0-∞) 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 (r 2 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 noninva- sive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19.

Original languageEnglish (US)
Pages (from-to)297-305
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number1
DOIs
StatePublished - Apr 1 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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