Interactions of Two Major Metabolites of Prasugrel, a Thienopyridine Antiplatelet Agent, With the Cytochromes P450

Rehmel, Jessica; Eckstein, James A.; Farid, Nagy A.; Heim, John B.; Kasper, Steve C.; Kurihara, Atsushi; Wrighton, Steven; Ring, Barbara J.

doi:10.1124/dmd.105.007989

Cited by 256 publications

(207 citation statements)

References 24 publications

(28 reference statements)

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“…It is also a prodrug that is predominantly metabolized by CYP3A4 and CYP2B6 [6,7]. Based on these properties, the pharmacology of prasugrel is less susceptible to CYP2C19 polymorphisms [8].…”

Section: Introductionmentioning

confidence: 99%

Risk of bleeding and repeated bleeding events in prasugrel-treated patients: a review of data from the Japanese PRASFIT studies

Nishikawa

Isshiki

Kimura

et al. 2017

Cardiovasc Interv and Ther

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Prasugrel is a third-generation thienopyridine that achieves potent platelet inhibition with less pharmacological variability than other thienopyridines. However, clinical experience suggests that prasugrel may be associated with a higher risk of de novo and recurrent bleeding events compared with clopidogrel in Japanese patients undergoing percutaneous coronary intervention (PCI). In this review, we evaluate the risk of bleeding in Japanese patients treated with prasugrel at the doses (loading/maintenance doses: 20/3.75 mg) adjusted for Japanese patients, evaluate the risk factors for bleeding in Japanese patients, and examine whether patients with a bleeding event are at increased risk of recurrent bleeding. This review covers published data and new analyses of the PRASFIT (PRASugrel compared with clopidogrel For Japanese patIenTs) trials of patients undergoing PCI for acute coronary syndrome or elective reasons. The bleeding risk with prasugrel was similar to that observed with the standard dose of clopidogrel (300/75 mg), including when bleeding events were re-classified using the Bleeding Academic Research Consortium criteria. The pharmacodynamics of prasugrel was not associated with the risk of bleeding events. The main risk factors for bleeding events were female sex, low body weight, advanced age, and presence of diabetes mellitus. Use of a radial puncture site was associated with a lower risk of bleeding during PCI than a femoral puncture site. Finally, the frequency and severity of recurrent bleeding events during continued treatment were similar between prasugrel and clopidogrel. In summary, this review provides important insights into the risk and types of bleeding events in prasugrel-treated patients.

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Section: Introductionmentioning

confidence: 99%

Risk of bleeding and repeated bleeding events in prasugrel-treated patients: a review of data from the Japanese PRASFIT studies

Nishikawa

Isshiki

Kimura

et al. 2017

Cardiovasc Interv and Ther

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show abstract

“…Eighty five percent of the pro-drug is transformed to an inactive metabolite by esterase, while the rest is changed into an active form by two, CYP-dependent, oxidative steps. In contrast, prasugrel is oxidized by CYP enzyme to its active metabolite in a single step, without an apparent dead-end inactive pathway, which may be the reason why responsiveness to it is independent of genotype as will be presented later [17]. The CYP2C19*2 allele carriers have higher a PR, as PR inhibition by the drug is insufficient.…”

Section: Genotyping -The Influence Of Gene Profile On Platelet Reactimentioning

confidence: 95%

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

Gajda¹,

Kołtowski²,

Tomaniak³

2015

Adv Clin Exp Med

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Aggregometry and genotyping are methods of platelet function testing, which can be beneficial for high-risk patients undergoing invasive cardiac procedures. An optimal level of platelet reactivity (PR) should be maintained. There are discrepancies between individuals and their response to clopidogrel, accounting for the incidence of poor responders from 5% to 44%. This phenomenon predisposes the patients to increased risk of ischaemic events and thereby overall poorer clinical outcome. Prasugrel and tricagrelor are newer without genetic correlation to their action, however associated with increased bleeding risk. Aggregometry methods assess platelet reactivity at the exact moment of blood sampling. They reflect "phenotype" of the patient and vary after drug administration or dose change. The most popular tests are Light Transmission Aggregometry, Vasodilator-Stimulated Protein, VerifyNow, Multiple Electrode Aggregometry and Thrombelastography. There is proven genetic correlation between some cytochrome enzymes on clopidogrel response. The most widely tested is gene CYP2C19, which produces the enzyme transforming clopidogrel into an active metabolite. The CYP2C19*2 allele carriers have higher PR which can result in more thrombotic events. The manuscript shows the most recent evidence behind platelet function testing. Aggregometry is shown to be beneficial in 5 trials and 1 meta-analysis, while one paper was of different opinion. Ten studies show a positive clinical effect of genotyping on patients' outcome, while one does not support it. The best method of identifying high-risk individuals could be both methods and personalisation of antiplatelet therapy may decrease adverse ischaemic outcomes (Adv Clin Exp Med 2015, 24, 4, 687-693).

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“…14 Cytochrome P (CYP) enzymes, principally 3A4 and 2B6, convert the thiolactone to the active metabolite R-138727. 10,[14][15][16] The parent molecule is not active in vitro. 13 Similarly, clopidogrel is converted from the inactive parent compound to the active metabolite via the CYP system in a 2-step process compared with one for prasugrel.…”

Section: Pharmacokinetics and Pharmacologymentioning

confidence: 99%

Critical Review of Prasugrel for Formulary Decision Makers

Schafer

Kjesbo²,

Gleason³

2009

JMCP

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Interactions of Two Major Metabolites of Prasugrel, a Thienopyridine Antiplatelet Agent, With the Cytochromes P450

Abstract: ABSTRACT:The biotransformation of prasugrel to R-138727 (2- [

Cited by 256 publications

References 24 publications

Risk of bleeding and repeated bleeding events in prasugrel-treated patients: a review of data from the Japanese PRASFIT studies

Risk of bleeding and repeated bleeding events in prasugrel-treated patients: a review of data from the Japanese PRASFIT studies

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

Critical Review of Prasugrel for Formulary Decision Makers

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