Abstract
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 metabolismby 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.
Key words
CAS 113665-84-2 - CAS 150322-43-3 - Clopidogrel - Cytochrome P450 - Drug interactions
- Omeprazole - Polymorphism - Prasugrel - Proton pump inhibitors