CMAJ • June 6, 2006; 174 (12). doi:10.1503/cmaj.060664.
© 2006 CMA Media Inc. or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.
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Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel

Jung-Won Suh, Bon-Kwon Koo, Shu-Ying Zhang, Kyung-Woo Park, Joo-Youn Cho, In-Jin Jang, Dong-Soon Lee, Dae-Won Sohn, Myoung-Mook Lee and Hyo-Soo Kim

From the Departments of Internal Medicine (Suh, Koo, Park, Sohn, Kim), Pharmacology (Cho, Jang) and Laboratory Medicine (Dong-Soon Lee), Seoul National University College of Medicine, Seoul, Korea; the Cardiovascular Center (Myoung-Mook Lee), Dong-Kook University Ilsan Hospital, Kyungki-do, Korea; and the Cardiovascular Laboratory (Kim), Clinical Research Institute, Seoul National University Hospital, Seoul, Korea


Figure 115
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  		Fig. 1: A: Adenine diphosphate (ADP) is an important physiologic agonist that plays a vital role in normal hemostasis and thrombosis. The P2Y12 receptor of platelets signals through a Galpha i coupled G-protein receptor (Gi2 coupled) and is important for potentiation of platelet activation mediated by other physiologic agonists, including collagen, von Willebrand factor and thromboxane A2.18 B: Inhibition of ADP-induced platelet aggregation by clopidogrel. Clopidogrel is a prodrug requiring metabolism by cytochrome P450 (CYP) 3A isoforms in order to be active. The active metabolite of clopidogrel blocks the platelet's P2Y12 receptor.19 Note: cAMP = cyclic adenosine monophosphate. Photo by: Lianne Friesen and Nicholas Woolridge

 

Figure 215
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  		Fig. 2: A: Cytochrome P450 (CYP) 3A4 and CYP3A5 are major isoforms of the CYP3A system. Total CYP3A activity accounts for 20% of all phase I reactions in the liver and metabolizes more than 50% of drugs. Under usual conditions, where both CYP3A4 and CYP3A5 contribute to total CYP3A activity, CYP3A4 is probably the main contributor. Therefore, the antiplatelet activity of clopidogrel may not differ substantially between patients with the CYP3A5 expressor genotype and those with the non-expressor genotype. B: In the presence of multiple substrates or inhibitors, CYP3A4 is more easily inhibited than CYP3A5, and therefore CYP3A5 becomes the main contributor to total CYP3A activity. In this condition, total CYP3A activity would differ depending on the patient's CYP3A5 genotype. Photo by: Lianne Friesen and Nicholas Woolridge

 

Figure 315
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  		Fig. 3: Platelet aggregation in healthy volunteers taking clopidogrel, by CYP3A5 genotype (non-expressor v. expressor).

 

Figure 415
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  		Fig. 4: Change in platelet aggregation from baseline after administration of clopidogrel, by CYP3A5 genotype.

 

Figure 515
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  		Fig. 5: Platelet aggregation in healthy volunteers taking clopidogrel after pretreatment with the CYP3A inhibitor itraconazole. NS = not significant.

 

Figure 615
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  		Fig. 6: Change in platelet aggregation from baseline after administration of clopidogrel and pretreatment with itraconazole.

 

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