Cytochrome P450 2C19 Genotype Status Research Articles

Abstract WP395: Verifynow P2Y12 Assay With Regard to Cytochrome P450 2C19 Polymorphisms and Stroke Recurrence

Background and Purpose: No evidence as yet that clopidogrel resistance (CR) on VerifyNow assay in relation to cytochrome P450 2C19 (CYP2C19) polymorphisms are more clinically informative at predicting recurrent vascular events during follow-up after ischemic stroke (IS). The aim of this study was to perform a subgroup analysis of MESTRO study to explore the relationship between VerifyNow P2Y12 assay with regard to CYP2C19 polymorphisms and stroke recurrence in patients with non-cardiogenic IS and clopidogrel treatment. Methods: The methods of the MAESTRO study have been published previously. For the study, CR was tested by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotype was classified as an ultrarapid metabolizer (UM; *1/*17, *17/*17), extensive metabolizer (EM; *1/*1), intermediate/unknown metabolizer (*1/*2, *1/*3 and *2/*17, *3/*17), or poor metabolizer (PM; *2/*2, *2/*3, *3/*3) based on CYP2C19 genotype status. UM or EM status patients were allocated into the good genotype group for clopidogrel metabolism, and intermediate/unknown metabolizer or PM status patients were allocated into the poor genotype group. Results: Of the 256 patients with clopidogrel treatment, 20 (7.8%) had a recurrent stroke: 15 (75%) experienced an IS and 5 (25%) experienced an ICH. Of the patients with percent inhibition (% INH) ≥40, the risk of recurrent stroke in the good genotype group was 2.2% and was not significantly different from that in the poor genotype group (6.7%) (P=0.400). There was also no significant reduction in the risk of a major vascular event between the groups (2.2% vs 6.7%, P=0.400). Of the patients with % INH <40, there was a trend towards reduction in risk for the recurrent stroke (2.1% vs 8.3%, p=0.142) and a major vascular event (2.1% vs 9.8%, p=0.081) in the good genotype group. Conclusions: Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel alone may not predict stroke recurrence.

Effects of Triflusal and Clopidogrel on the Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping.

Background and Purpose To compare the efficacy and safety of antiplatelet agents for the secondary prevention of ischemic stroke based on cytochrome P450 2C19 (CYP2C19) polymorphisms. Methods This study was a prospective, multicenter, randomized, parallel-group, open-label, blind genotype trial. First time non-cardiogenic ischemic stroke patients were enrolled and screened within 30 days. Participants were randomized to receive either triflusal or clopidogrel for secondary stroke prevention. The primary outcome was the time from randomization to first recurrent ischemic stroke or hemorrhagic stroke. Results The required sample size was 1,080 but only 784 (73%) participants were recruited. In patients with a poor CYP2C19 genotype for clopidogrel metabolism (n=484), the risk of recurrent stroke among those who received triflusal treatment was 2.9% per year, which was not significantly different from those who received clopidogrel treatment (2.2% per year; hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.60–2.53). In the clopidogrel treatment group (n=393), 38% had good genotypes and 62% poor genotypes for clopidogrel metabolism. The risk of recurrent stroke in patients with a good CYP2C19 genotype was 1.6% per year, which was not significantly different from those with a poor genotype (2.2% per year; HR, 0.69; 95% CI, 0.26–1.79). Conclusions Whilst there were no significant differences between the treatment groups in the rates of stroke recurrence, major vascular events, or coronary revascularization, the efficacy of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype status remains unclear.

Effect of the CYP2C19 polymorphism on the eradication rate of Helicobacter pylori infection by 7‐day triple therapy with regular proton pump inhibitor dosage

Proton pump inhibitors (PPI) are mainly metabolized by cytochrome P450 2C19 (CYP2C19) in the liver. We investigated whether the CYP2C19 genotype plays a role in the eradication rate of Helicobacter pylori (H. pylori) infection in patients receiving pantoprazole- or esomeprazole-based triple therapy. A total of 327 patients infected with H. pylori were treated with either pantoprazole or esomeprazole, plus amoxicillin and clarithromycin for 7 days. The presence of the CYP2C19 genotype was determined by pyrosequencing. The overall H. pylori eradication rate was 85%; 82.6% for the PAC regimen, and 88.3% for the EAC regimen; the differences were not statistically significant. The overall eradication rate in the poor metabolizer groups (PM) was significantly higher than in the extensive metabolizer groups (EM) (97.4% vs 83.3%; P = 0.016). The eradication rates in the EM and PM groups were 80.8% and 95.7% for the PAC regimen and 86.8% and 100% for the EAC regimen, respectively. The results of this study suggest that the CYP2C19 genotype status may play a role in the H. pylori eradication rate in patients receiving pantoprazole or esomeprazole-based triple therapy.

T1079 Acid Inhibition in Early Phase By Intravenous Infusion of Omeprazole and/or Famotidine in Relation to Cytochrome P450 2C19 Genotype Status

T1079 Acid Inhibition in Early Phase By Intravenous Infusion of Omeprazole and/or Famotidine in Relation to Cytochrome P450 2C19 Genotype Status

Initial 48-hour acid inhibition by intravenous infusion of omeprazole, famotidine, or both in relation to cytochrome P450 2C19 genotype status

Faster and stronger acid inhibition is required for the treatment of hemorrhage from peptic ulcers. We compared the effects of intravenous infusion regimens of a proton pump inhibitor (PPI) alone, a histamine 2 receptor antagonist (H2RA) alone, and the combination of a PPI with an H2RA on acid inhibition in the early postadministration phase in relation to cytochrome P450 (CYP) 2C19 genotype status. Fifteen Helicobacter pylori-positive volunteers with 3 different CYP2C19 genotypes were administered twice-daily intravenous infusions of 20 mg famotidine alone, 20 mg omeprazole alone, 10 mg omeprazole plus 10 mg famotidine (half-concomitant regimen), and 20 mg omeprazole plus 20 mg famotidine (full-concomitant regimen) for 2 days. The subjects underwent 48-hour intragastric pH monitoring. In homozygous extensive metabolizers (EMs) the median first 24-hour intragastric pH with the full-concomitant regimen was 4.8 (range, 4.5-5.4), which was significantly higher than that with omeprazole alone (3.9 [range, 2.6-4.7], P=.043) or famotidine alone (4.4 [range, 3.8-4.9], P=.043). In heterozygous EMs and poor metabolizers the respective median first 24-hour pH values attained with omeprazole alone (5.8 [range, 4.3-6.3] and 6.1 [range, 5.3-7.4]) and the full-concomitant regimen (5.8 [range, 5.1-6.4] and 5.8 [range, 5.4-6.2]) were significantly higher than those attained with famotidine alone (4.1 [range, 3.9-6.5] and 4.7 [range, 3.7-5.7], P=.043 for all). For faster and stronger acid inhibition, the concomitant infusion regimen of a PPI and an H2RA appears to be therapeutically useful in homozygous and heterozygous EMs, but omeprazole alone appears to be sufficient in poor metabolizers of CYP2C19.

Effect of high‐dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19

Backgrounds and AimLansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid‐inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem.MethodsEighteen Helicobacter pylori3‐negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24‐hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24‐hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily.ResultsWhen lansoprazole 30 mg was given once daily, the mean 24‐hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P < .005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24‐hour intragastric pH value was 7.4.ConclusionThe effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.Clinical Pharmacology & Therapeutics (2001) 70, 484–492; doi: 10.1016/S0009‐9236(01)28055‐2