Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel <i>in vitro</i>

Zahno, Anja; Brecht, Karin; Bodmer, Michael; Bur, Daniel; Tsakiris, Dimitrios Α.; Krähenbühl, Stephan

doi:10.1111/j.1476-5381.2010.00881.x

Cited by 45 publications

(39 citation statements)

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“…Formation of the oxo intermediate alone is undetectable in the current study. On the other hand, the finding in this study with CYP3A4 and clopidogrel is consistent with other studies, which showed that CYP3A4 could convert clopidogrel to AM and that the carboxylic acid of clopidogrel is inactive in this assay (Zahno et al, 2010). Figure 6 summarizes the findings of this study and compares the results to what is known in the literature concerning oxo-prasugrel conversion.…”

Section: Discussionsupporting

confidence: 82%

“…SR-26334 is inactive as a P2Y 12 antagonist either directly or after exposure to cytochromes P450. Whether this is because SR-26334 is a poor substrate for cytochrome P450 oxidation or because the ring-opened version of the carboxylic acid is a poor antagonist for the platelet P2Y 12 receptor is unclear, although recent work suggests the former to be the case (Zahno et al, 2010). Metabolic activation of prasugrel, a relatively new choice for antiplatelet therapy, follows a somewhat similar pathway, which involves cleavage of the ester linkage to form the oxo intermediate [2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone] (R-95913) followed by ring opening to the AM, 2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene acetic acid (R-138727) (Sugidachi et al, 2001;Hasegawa et al, 2005).…”

Section: Introductionmentioning

confidence: 96%

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Dissecting the Activation of Thienopyridines by Cytochromes P450 Using a Pharmacodynamic Assay In Vitro

Abell¹,

Liu²

2011

J Pharmacol Exp Ther

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The thienopyridine antiplatelet drugs, such as ticlopidine, clopidogrel, and prasugrel, require activation by cytochromes P450 in vivo to effectively block platelet aggregation. The study of the metabolic activation of these compounds has been hampered by the lability and reactivity of the ring-opened active metabolite (AM) and by the numerous metabolites that can be formed in such a transformation. We have developed a novel method whereby platelets are incubated with the cytochrome P450 and the thienopyridine of interest for various amounts of time, and the effects on ADP-driven platelet aggregation are directly examined. In this way, the platelet is used as a biosensor for detection of the AM. Using this method, cytochromes P450 capable of converting clopidogrel, prasugrel, and 2-oxo-clopidogrel to metabolites that inhibit ADP-induced platelet aggregation were identified as well as which cytochromes P450 were capable of catalyzing partial reactions (e.g., conversion of 2-oxo-clopidogrel to the AM). These studies show that, in vitro, CYP3A4/5, 2C19, and 2B6 are individually capable of converting clopidogrel and prasugrel to the AM and that the cytochrome P450 preference for these two thienopyridines is very similar.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 96%

Dissecting the Activation of Thienopyridines by Cytochromes P450 Using a Pharmacodynamic Assay In Vitro

Abell¹,

Liu²

2011

J Pharmacol Exp Ther

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“…Moreover, simvastatin was shown to be a stronger inhibitor than atorvastatin. 19 This finding can be explained by the difference in the chemical structure of simvastatin and atorvastatin.…”

Section: Clopidogrel and Lipophilic Statins Co-medicationmentioning

confidence: 95%

Clopidogrel and the possibility of drug–drug interaction in primary health care

Urtane¹,

Aitullina²,

Pukite³

2013

Journal of Young Pharmacists

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a b s t r a c tIntroduction: Clopidogrel ineffectiveness is a serious problem in antiplatelet therapy. Many factors may contribute to this phenomenon. One of them is clopidogrel drugedrug interaction with CYP2C19 and CYP3A4 enzyme inhibitors. The main goal of this descriptive study was to assess the prevalence of cases of clopidogreledrug interactions in the primary health care physicians' practices. Materials and methods: During 2010e2011, 80 patients receiving clopidogrel antiplatelet therapy from primary care physicians' clinical practices were involved in this study. By using questionnaires and case histories, the following information was collected: Age, gender, clinical diagnoses, and medications used.Results: In the current study, drugs were used that could potentially influence the effect of clopidogrel: Omeprazole, lipophilic statins, calcium channel blockers (CCB). There was a different use of the abovementioned drugs before and after the initiation of the clopidogrel therapy, e.g., 12 (15.0%) and 44 (55.0%) patients used proton pump inhibitors (PPI) before and after the clopidogrel therapy accordingly (P ¼ 0.16; c 2 ¼ 1.91). However, pantoprazole was recommended more often than other PPI. The use of the potential CYP3A4 inhibitors e lipophilic statins and CCB e was increased after the prescription of clopidogrel too. Concomitant use of statins (mainly atorvastatin) with clopidogrel was observed in 75 (93.8%) patients and the use of CCB (mainly amlodipine) e in 33 (41.3%) patients. Conclusion: In the primary health care practices, it is revealed that there is co-medication of clopidogrel with weak CYP3A4 inhibitors, such as lipophilic statins and amlodipine, and with the moderate CYP2C19 inhibitor e omeprazole. The latter co-medication is potentially harmful and it is very important to inform the first care professionals about the opportunity to change omeprazole to pantoprazole, which does not influence clopidogrel biotransformation.

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“…9 Discrepancies in the antiplatelet effect of clopidogrel may be related to differences in the timing of each study, the latter studies being conducted immediately after PCI and with a loading dose of clopidogrel, and an exact time of daily administration of clopidogrel and CYP3A4 metabolized statins. 10 Finally, in a recent subanalysis of the TRITON-TIMI 38 study there was no influence of concomitant use of statins or calcium-channel blocker on clinical outcome in patients treated with either clopidogrel or prasugrel. 11 Thus, the influence of drug-drug interactions on the pharmacodynamic effect of clopidogrel and clinical outcome is still controversial.…”

Section: Article P 679mentioning

confidence: 99%

The Clopidogrel-Statin Interaction

Tantry

Jeong

Gurbel

2014

Circ J

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592TANTRY US et al. Circulation JournalOfficial Journal of the Japanese Circulation Society http://www. j-circ.or.jp activity in influencing the antiplatelet effect of clopidogrel came from the work of Lau et al. 4,5 Over a decade ago, those authors demonstrated that atorvastatin co-administration attenuated the antiplatelet effect of clopidogrel and the pharmacologic modulation of CYP 3A4 activity directly influenced the pharmacodynamic effect of clopidogrel. That ground breaking study opened the "Pandora's box" of the clopidogrel response variability phenomenon related to drug-drug interactions. The phenomenon of clopidogrel response variability and resistance paved the way for the concept of personalized antiplatelet therapy. Now, platelet function (PF) testing to ensure optimal platet is well established that clopidogrel therapy is associated with a widely variable pharmacodynamic response whereby approximately 1 in 3 patients will have high platelet reactivity (HPR), which has been strongly linked to the occurrence of post-PCI ischemic events. In addition to the presence of CYP2C19 loss-of-function allele (LoF) carriage, a diminished antiplatelet response to clopidogrel has been associated with co-administration of proton-pump inhibitors, lipophilic statins, and calcium-channel blockers that share either CYP2C19 or CYP3A4 isoenzymes with clopidogrel for their metabolism. Proposed mechanism for clopidogrel-atorvastatin interaction in patients with high levels of on-clopidogrel platelet reactivity. HPR, high platelet reactivity.

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Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro

Cited by 45 publications

References 45 publications

Dissecting the Activation of Thienopyridines by Cytochromes P450 Using a Pharmacodynamic Assay In Vitro

Dissecting the Activation of Thienopyridines by Cytochromes P450 Using a Pharmacodynamic Assay In Vitro

Clopidogrel and the possibility of drug–drug interaction in primary health care

The Clopidogrel-Statin Interaction

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