PT - JOURNAL ARTICLE AU - Zeruesenay Desta AU - Anil Modak AU - Phuong D. Nguyen AU - Suzanne M. Lemler AU - Yasuhisa Kurogi AU - Lang Li AU - David A. Flockhart TI - Rapid Identification of the Hepatic Cytochrome P450 2C19 Activity Using a Novel and Noninvasive [<sup>13</sup>C]Pantoprazole Breath Test AID - 10.1124/jpet.108.147751 DP - 2009 Apr 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 297--305 VI - 329 IP - 1 4099 - http://jpet.aspetjournals.org/content/329/1/297.short 4100 - http://jpet.aspetjournals.org/content/329/1/297.full SO - J Pharmacol Exp Ther2009 Apr 01; 329 AB - 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 &lt; 0.01); linear regression analysis indicated a gene-dose effect relationship (r2 ranged between 0.236 and 0.522; all p &lt; 0.05). These breath test indices were significantly lower in PMs than IMs (p &lt; 0.05) or EMs (p &lt; 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. The American Society for Pharmacology and Experimental Therapeutics