CMAJ • January 30, 2007; 176 (3). doi:10.1503/cmaj.1060227.
© 2007 Canadian Medical Association 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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Letters

Atherothrombotic events and clopidogrel therapy

Jung-Won Suh, Bon-Kwon Koo and Hyo-Soo Kim

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

[Three of the authors respond:]

We thank Micheal Guirguis for his valuable comments on our paper.1 One of the limitations of our work, which we discussed in the article, was that we did not assay the active metabolite of clopidogrel directly but, rather, performed a platelet aggregation test with adenosine diphosphate as an indirect marker of the active clopidogrel metabolite, as done by previous investigators. Therefore, we were not able to rule out the involvement of factors other than the interaction of the active metabolite and the platelet adenosine diphosphate receptor.

We agree with Guirguis that pharmacokinetic–pharmacodynamic data are needed to confirm individual variations in clopidogrel metabolism. However, such data have not yet been collected because of the difficulty in assaying the active metabolite of clopidogrel. Some researchers are investigating clopidogrel metabolism using various methods,2–4 and we are looking forward to applying their findings to clinical studies in the near future.

We appreciate the suggestion by Craig McLachlan and associates of the possibility of rebound atherothrombotic events after cessation of clopidogrel administration in susceptible people, such as those with the non-expressor genotype for the 3A5 isoenzyme of the cytochrome P450 3A system. In our study, patients in the non-expressor group experienced more atherothrombotic events than those in the expressor group, and events after 1 month occurred only in the non-expressor group. However, all patients who experienced atherothrombotic events after 1 month were taking both clopidogrel and ASA at the time. Therefore, our data cannot be used to address the issue of whether people with the non-expressor genotype for the 3A5 isoenzyme of the cytochrome P450 3A system may be more vulnerable to atherothrombotic events after cessation of clopidogrel administration. However, it is possible that these patients are more sensitive to rebound effects on platelet aggregation in the setting of inhibition of the CYP3A4 isoenzyme. The issue raised by McLachlan and associates is an important one and warrants further study.

REFERENCES

  1. Suh JW, Koo BK, Zhang SY, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 2006;174:1715-22.[Abstract/Free Full Text]
  2. Taubert D, Kastrati A, Harlfinger S, et al. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost 2004;92:311-6.
  3. Ksycinska H, Rudzki P, Bukowska-Kiliszek M. Determination of clopidogrel metabolite (SR26334) in human plasma by LC-MS. J Pharm Biomed Anal 2006;41:533-9.[CrossRef][Medline]
  4. Souri E, Jalalizadeh H, Kebriaee-Zadeh A, et al. Validated HPLC method for determination of carboxylic acid metabolite of clopidogrel in human plasma and its application to a pharmacokinetic study. Biomed Chromatogr 2006;20:1309-14.[CrossRef][Medline]




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