This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gladding, P. Articles by Dahl, M.-L. Search for Related Content PubMed Articles by Gladding, P. Articles by Dahl, M.-L. Related Collections Related Article

The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response

An Analysis From the PRINC (Plavix Response in Coronary Intervention) Trial

Patrick Gladding, FRACP^_*,_*, Mark Webster, FRACP^_*, Irene Zeng, MSc^_*, Helen Farrell, BHSc^_*, Jim Stewart, FRACP^_*, Peter Ruygrok, FRACP^_*, John Ormiston, FRACP^_*, Seif El-Jack, FRACP^_*, Guy Armstrong, FRACP^_*, Patrick Kay, FRACP^_*, Douglas Scott, FRACP^_*, Arzu Gunes, MD, PhD, Marja-Liisa Dahl, MD, PhD

^_* Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden

^_* Reprint requests and correspondence: Dr. Patrick Gladding, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92 024, Auckland 1030, New Zealand (Email: patrickg{at}adhb.govt.nz).

Objectives: This study assessed the effect of pharmacogenetics on the antiplatelet effect of clopidogrel.

Background: Variability in clopidogrel response might be influenced by polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP] family), transport proteins (P-glycoprotein) and/or target proteins for the drug (adenosine diphosphate–receptor P2Y12).

Methods: Sixty patients undergoing elective percutaneous coronary intervention in the randomized PRINC (Plavix Response in Coronary Intervention) trial had platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage. Polymerase chain reaction–based genotyping evaluated polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes.

Results: CYP2C19*1*1 carriers had greater platelet inhibition 2 h after a 600-mg dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in CYP2C19*2 or *4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C19*17 carriers (9%, 0% to 98%, p = 0.026). CYP2C19*2 or *4 carriers had greater platelet inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8% to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042).

Conclusions: Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583)

Key Words: clopidogrel • pharmacogenetics • antiplatelets

Abbreviations and Acronyms   CYP = cytochrome P450   i = intronic   PCI = percutaneous coronary intervention   SNP = single nucleotide polymorphism

Related Article

Searching for the Ceiling: New Reflections on the Disposition and Metabolism of Clopidogrel

Neal S. Kleiman
J. Am. Coll. Cardiol. Intv. 2008 1: 628-630. [Full Text] [PDF]

This article has been cited by other articles:

				N. S. Kleiman Searching for the Ceiling: New Reflections on the Disposition and Metabolism of Clopidogrel J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 628 - 630. [Full Text] [PDF]

				S. B. King III and K. M. Momary Thienopyridines: Time for Personalized Therapy? J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 718 - 719. [Full Text] [PDF]