Prediction of Clopidogrel Low Responders by a Rapid CYP2C19 Activity Test

Abstract

Aim: Clopidogrel, an essential drug for the prevention of stent thrombosis, is a prodrug activated by CYP enzyme family including CYP2C19. It is known that activity-defective polymorphisms of CYP2C19 (CYP2C19 2 and 3) are associated with reduced clopidogrel efficacy and poor prognosis. Recently, the 13 C-pantoprazole breath test is developed to evaluate the CYP2C19 activity. The aim of this study is to evaluated the efficiency of the CYP2C19 activity test as a predictor of antiplatelet effect of clopidogrel Methods: The CYP2C19 activity and the antiplatelet effect of clopidogrel were evaluated in 27 healthy volunteers. Change of the carbon isotope ratios ( 13 CO2/ 12 CO2) in expiration gas between before and after 13 C-pantoprazole intake was evaluated as delta over baseline (DOB) ratio (‰).

CYP2C19 Phenoconversion by Routinely Prescribed Proton Pump Inhibitors Omeprazole and Esomeprazole: Clinical Implications for Personalized Medicine

“…The average intrapatient interday variability in CYP2C19 phenotype (n 5 31) determined by Ptz-BT was considerably low (coefficient of variation, 17%) (Supplemental Table 2). From the average DOB Tmax and DOB Cmax of breath samples collected at 20, 30, and 40 minutes for all 31 volunteers/CAD patients, it was determined that the DOB at 30 minutes (DOB 30 ) reflected the CYP2C19 phenotype (Supplemental Table 3), which is consistent with all previous studies (Desta et al, 2009;Furuta et al, 2009Furuta et al, , 2010Thacker et al, 2011Thacker et al, , 2013Tazaki et al, 2012).…”

“…The patient's current CYP2C19 enzymatic status (phenotype) would be a far better tool for personalized medicine than the genotype test. The Ptz-BT can serve as a safe, rapid, and noninvasive in vivo phenotype marker of CYP2C19 activity (Desta et al, 2009;Furuta et al, 2009Furuta et al, , 2010Thacker et al, 2011Thacker et al, , 2013Tazaki et al, 2012).…”

“…From previous studies (Desta et al, 2009;Furuta et al, 2009Furuta et al, , 2010Thacker et al, 2011Thacker et al, , 2013Tazaki et al, 2012), correlating CYP219 genotype and phenotype using pantoprazole metabolites in plasma, the DOB 30 cutoff values for the Ptz-BT were set at ,1.2‰ for PMs, 1.2-3.4‰ for intermediate metzbolizers (IMs), $3.5 to 7‰ for extensive metabolizers (EMs), and .7‰ for ultrarapid metabolizers (UMs). There was a genotype-phenotype discordance in 19 of 31 subjects at baseline prior to PPI therapy (61%); all 7 UMs by genotype were EMs by phenotype, 5 of 12 EMs by genotype were IMs by phenotype, 4 of 10 IMs by genotype were EMs by phenotype, and 3 of 10 IMs by genotype were PMs by phenotype.…”

“…C breath test (Ptz-BT) has a number of practical advantages-it captures genetic and nongenetic factors that can alter CYP2C19 enzyme activity, and it is safe, easy, noninvasive, and rapid (30 minutes) to perform in a point-of-care setting (Desta et al, 2009;Furuta et al, 2009Furuta et al, , 2010Thacker et al, 2011Thacker et al, , 2013Tazaki et al, 2012). It has the potential to offer greater clinical utility compared with the existing genetic test for personalizing medicine for gastroesophageal reflux disease, antiplatelet therapy (Kushner et al, 2009), and Helicobacter pylori eradication therapy (Kuo et al, 2014).…”

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…Kodaira et al found a significant correlation between AUC 0-3h of DOB 13 CO 2 / 12 CO 2 ratios and both plasma [ 13 C]-aminopyrine AUC 0-3h and clearance [123]. [ 13 C]-pantoprazole has been proposed as an alternative CYP2C19 phenotyping probe, as several studies found significantly lower DOB values in CYP2C19 poor metabolizers compared to intermediate or extensive metabolizers [124][125][126][127][128][129]. In addition, plasma [ 13 C]-pantoprazole AUC correlated significantly with the AUC of DOB 13 [130].…”