PMID- 19537521
OWN - NLM
STAT- MEDLINE
DCOM- 20090911
LR  - 20181201
IS  - 0004-4172 (Print)
IS  - 0004-4172 (Linking)
VI  - 59
IP  - 5
DP  - 2009
TI  - Relevance of metabolic activation pathways: the example of clopidogrel and 
      prasugrel.
PG  - 213-27
LID - 10.1055/s-0031-1296388 [doi]
AB  - Poor or lacking responses to the antiplatelet effect of clopidogrel (CAS 
      113665-84-2) and the attendant clinical consequences have been a growing concern 
      for several years. This debate has been invigorated by reports suggesting the 
      ability of inhibitors of the cytochrome P450 isoenzyme, CYP 2C19, to interfere 
      with clopidogrel efficacy. In the present review, the mechanisms underlying 
      clopidogrel failure are analyzed, based on an overview of the current perceptions 
      of drug metabolism by the CYP superfamily of enzymes, and paying particular 
      attention to the relevant properties of the newly introduced thienopyridine, 
      prasugrel (CAS 150322-43-3). Convincing evidence indicates that the vulnerability 
      of clopidogrel lies in its mode of activation. In a two-step sequence, both 
      crucially dependent on the function of CYP 2C19, about 15% of a given dose of 
      clopidogrel are converted into an active metabolite. Thus, activation is at risk 
      or impossible in patients with the phenotype of an intermediate or poor 
      metabolizer or, for similar reasons, in patients co-administered with a CYP 2C19 
      inhibitor such as the proton pump inhibitor (PPI), omeprazole. Theoretical and 
      experimental data suggest that other PPIs such as rabeprazole do not share this 
      ability. As opposed to clopidogrel, administered prasugrel is practically 
      completely activated. At first sight a similar two-step process, this activation 
      shows distinct differences: The first metabolic step is mediated by 
      carboxylesterases and the second reaction is catalyzed by five different CYP 
      isoenzymes, with no pivotal role for CYP 2C19 or any other CYP isoform. This 
      setting allows the prediction that neither specific genetic traits nor 
      pharmacokinetic drug interactions will interfere with prasugrel antiplatelet 
      activity. Unfolding evidence, including a lack of interference by genotype and 
      CYP 2C19 or CYP 3A4 inhibitors, has confirmed this expectation. The robust 
      efficacy of prasugrel allows the prediction that this new thienopyridine will 
      provide an unproblematic treatment modality, with no need for pheno- or 
      genotyping and no special regards for co-administered drugs.
FAU - Petersen, Karl-Uwe
AU  - Petersen KU
AD  - Department of Pharmacology and Toxicology, RWTH Aachen University, Aachen, 
      Germany. karluwe.petersen@post.rwth-aachen.de
LA  - eng
PT  - Journal Article
PL  - Germany
TA  - Arzneimittelforschung
JT  - Arzneimittel-Forschung
JID - 0372660
RN  - 0 (Piperazines)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - 0 (Thiophenes)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - A74586SNO7 (Clopidogrel)
RN  - G89JQ59I13 (Prasugrel Hydrochloride)
RN  - OM90ZUW7M1 (Ticlopidine)
SB  - IM
MH  - Animals
MH  - Biotransformation/*drug effects/*genetics
MH  - Clopidogrel
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Genetic Variation
MH  - Humans
MH  - Piperazines/*pharmacokinetics/*pharmacology
MH  - Platelet Aggregation Inhibitors/adverse effects/*pharmacokinetics/*pharmacology
MH  - Prasugrel Hydrochloride
MH  - Thiophenes/*pharmacokinetics/*pharmacology
MH  - Ticlopidine/adverse effects/*analogs & derivatives/pharmacokinetics/pharmacology
EDAT- 2009/06/23 09:00
MHDA- 2009/09/12 06:00
CRDT- 2009/06/23 09:00
PHST- 2009/06/23 09:00 [entrez]
PHST- 2009/06/23 09:00 [pubmed]
PHST- 2009/09/12 06:00 [medline]
AID - 10.1055/s-0031-1296388 [doi]
PST - ppublish
SO  - Arzneimittelforschung. 2009;59(5):213-27. doi: 10.1055/s-0031-1296388.