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n arterial thrombus formation, the interaction of adenosine diphosphate (ADP) with its receptor P2Y12 plays an important role in platelet activation and its maintenance. [1][2][3][4] Dual antiplatelet therapy with aspirin and thienopyridine derivative is the standard therapy for the prevention of stent thrombosis in patients after percutaneous coronary intervention (PCI). [5][6][7][8] Ticlopidine, a 1st-generation P2Y12 ADP receptor antagonist, has been reported to have a relative high rate of side-effects. 9 Clopidogrel, a 2nd-generation P2Y12 ADP receptor antagonist, has been demonstrated to reduce the risk of cardiovascular events in patients with prior vascular diseases, 10,11 and is widely used for secondary prevention in patients with coronary artery disease. However, it is well known that clopidogrel exerts little antiplatelet effect in a certain proportion of patients, a phenomenon termed "clopidogrel resistance". 12-15 Importantly, cardiovascular risk is elevated after coronary stent implantation in patients with clopidogrel resistance. 16 Clopidogrel is a prodrug that requires two-step biotransformation processes mediated mainly by 2 cytochrome p450 enzymes (CYP), CYP2C19 and CYP3A4. 17,18 Two major single nucleotide polymorphisms (SNPs) of CYP2C19 are known to make the enzyme activity non-functional. 19,20 One is CYP2C19*2, which is the mutation of guanine to adenine at position 681 in exon 5, causing a splicing defect, 19 and the other is CYP2C19*3, which is the mutation of guanine to adenine at position 636 in exon 4, forming a stop codon. 20 The frequency of the CYP2C19*2 or *3 mutation varies among races. The frequency of CYP2C19*2 in Asians is higher (30%) than in Western people (~15%), whereas the CYP2C19*3 allele has been reported as frequent in Asians (~5%) and rare in Caucasians (0.04%). 21 Results of a recent study of healthy volunteer subjects showed that CYP2C19 polymorphisms are associated with a weaker antiplatelet response to clopidogrel. 22 Furthermore, the plasma concentration of the active metabolite of clopidogrel is affected by CYP2C19 genotype. 23 However, to our knowledge no study has evaluated the effect of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in actual clinical patients with cardiovascular risks on aspirin therapy. The SNP of CYP3A4 (IVS10 +12G>A) has been reported to enhance the antiplatelet effect of clopidogrel, 24 and the SNP of P2Y12 (T744C) has been reported to reduce the antiplatelet effect of clopidogrel when it coexists with CYP2C19 SNPs. 25 We recently systematically evaluated the antiplatelet effect of clopidogrel during low-dose aspirin therapy in 30 Japanese patients scheduled for PCI, and reported a wide inter-individual variation in the antiplatelet effect of clopidogrel, with 4 cases (14%) being classified as non-responders. 26 Comparison of our data with results from a similar study performed in the US 27 also showed that the effectiveness of Background: The P2Y12 adenosine diphosphate (ADP) receptor blocker, clopidogrel, an essential...

Background Dual antiplatelet therapy with acetylsalicylic acid (ASA) and a P2Y12 ADP-receptor blocker is standard for prevention of coronary stent thrombosis. Clopidogrel, a 2 nd -generation P2Y12 blocker, has recently become available in Japan and this study aimed to evaluate its antiplatelet effects in Japanese patients. Methods and ResultsThirty Japanese patients scheduled for elective coronary stent implantation were enrolled. Under low-dose ASA therapy, 300 mg clopidogrel was loaded on the 1 st day and a daily 75-mg dose was administered on the following days. Assessed by optical aggregometer, rapid inhibition occurred at 4 h, when the inhibition of platelet aggregation rate (IPA) was 16.4±12.8% using 5 μmol/L ADP as the stimulus. The antiplatelet efficacy of clopidogrel was reasonably constant in each patient throughout the study period, although there was a broad inter-individual variation. At 48 h after clopidogrel loading, the ratios of responders (IPA ≥30%), hypo-responders (10%≤IPA<30%), and non-responders (IPA <10%) were 36%, 50%, and 14%, respectively. Conclusions The antiplatelet effectiveness of clopidogrel appeared individual-specific with wide inter-individual variation. The rate of clopidogrel non-responders was 14% among the examined Japanese patients. (Circ J 2009; 73: 336 -342)

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SUMMARYBackground 13 CO 2 is produced on metabolism of 13 C-labelled-pantoprazole ([ 13 C]-pantoprazole) by CYP2C19. AimTo investigate whether the [13 C]-pantoprazole breath test can predict CYP2C19 status and efficacy of proton pump inhibitors (PPIs) in Japanese. MethodsWe classified 110 healthy volunteers as rapid metabolizers (RM), intermediate metabolizers (IM) or poor metabolizers (PM) of CYP2C19 by genotyping. Breath samples were collected at 10-min intervals for 60 min after dosing with 100 mg [13 C]-pantoprazole. Changes in the carbon isotope ratios ( 13 CO 2 ⁄ 12 CO 2 ) in carbon dioxide in breath samples were measured and expressed as a delta-over-baseline (DOB) ratio (&). Of the 110 subjects, twenty-two randomly selected subjects underwent intragastric pH monitoring on day 7 of dosing with 30 mg of lansoprazole. ResultsThe DOB values of RMs were the highest and those of PMs the lowest of the three groups. Statistically significant differences were observed in the area-under-the-curve (AUC) 20-60 min of DOB among the three groups. The mean 24-h intragastric pHs attained by lansoprazole 30 mg for 7 days were inversely correlated with the AUC 20-60 min of DOB. Conclusions