Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease.
OBJECTIVE
The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.


RESULTS
Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses.


CONCLUSIONS
Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.
Varenhorst
Christoph
C
Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden. christoph.varenhorst@ucr.uu.se
James
Stefan
S
Erlinge
David
D
Brandt
John T
JT
Braun
Oscar O
OO
Man
Michael
M
Siegbahn
Agneta
A
Walker
Joseph
J
Wallentin
Lars
L
Winters
Kenneth J
KJ
Close
Sandra L
SL
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001241:Aspirin / Q000627:therapeutic use*; D000077144:Clopidogrel; D003327:Coronary Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068799:Prasugrel Hydrochloride; D013876:Thiophenes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine; D001241:Aspirin