title: CYP3A4 genetic status may be associated with increased vulnerability to the inhibitory effect of calcium-channel blockers on clopidogrel.
abstract: BACKGROUND
  Calcium-channel blockers (CCBs) inhibit the CYP3A4 enzyme, which is involved in clopidogrel activation. Studies have shown conflicting results regarding the effect of concomitant CCB administration on clopidogrel response. We investigated the relationship between CYP3A4 genotype and the inhibitory effect of CCBs on clopidogrel response.
  
  
  RESULTS
  Clopidogrel on-treatment platelet reactivity (OPR) was measured and CYP3A4 (IVS10+12G>A) genotyped in 1,247 consecutive patients with drug-eluting stent implantation. The mean OPR was 231±83 (P2Y12 reaction units: PRU). In total, 332 (26.6%) CCB users had higher OPR compared with 915 (73.4%) non-CCB users (245±84 vs. 227±83 PRU, P=0.001). The distribution of CYP3A4 (IVS10+12G>A) genotype was 63.6%, 32.6% and 3.8% for GG, GA and AA genotypes, respectively. After adjustment for possible confounding factors, the number of A-alleles was associated with increased vulnerability to CCB use (effect of CCB use ΔPRU: +8 PRU, P=0.210, +24 PRU, P=0.012, +50 PRU, P=0.025, for patients with 0, 1, and 2 A-alleles, respectively, +24 PRU, P=0.005 for GA/AA genotypes). Furthermore, only in the GA/AA-genotype did CCB use result in a significantly increased risk for high-OPR (odds ratio 1.84, 95% confidence interval 1.15-2.92, P=0.010).
  
  
  CONCLUSIONS
  CCB use is associated with increased OPR. The number of CYP3A4 (IVS10+12G>A) A-alleles may be associated with an increased vulnerability to the effects of CCBs on clopidogrel response variation.
authors: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea.
authors: Jin Joo
authors: JJ
authors: Park
authors: Kyung Woo
authors: KW
authors: Park
authors: Jeehoon
authors: J
authors: Kang
authors: Ki-Hyun
authors: KH
authors: Jeon
authors: Si-Hyuck
authors: SH
authors: Kang
authors: Hyo Suk
authors: HS
authors: Ahn
authors: Jung-Kyu
authors: JK
authors: Han
authors: Jin-Sin
authors: JS
authors: Koh
authors: Sang Eun
authors: SE
authors: Lee
authors: Han-Mo
authors: HM
authors: Yang
authors: Hae-Young
authors: HY
authors: Lee
authors: Hyun-Jae
authors: HJ
authors: Kang
authors: Bon-Kwon
authors: BK
authors: Koo
authors: Byung-Hee
authors: BH
authors: Oh
authors: Young-Bae
authors: YB
authors: Park
authors: Hyo-Soo
authors: HS
authors: Kim
mesh_terms: D000368:Aged; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D010979:Platelet Function Tests; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D012307:Risk Factors; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine