Reply to: "Paraoxonase-1 and clopidogrel efficacy"

Cytochrome P450-Activated Prodrugs

“…Their results suggest that the oxidative pathway is the dominant one. Nevertheless, based on a study of the drug in patients, the proponents of the PON-1 activation step have argued that it is, in fact, the critical one [84]. …”

Clinical Application of CYP2C19 Pharmacogenetics Toward More Personalized Medicine

“…In addition, an improved protective effect of clopidogrel after myocardial infarction has been observed in patients carrying the CYP2C19*17 allele (Tiroch et al, 2010). The major enzymes involved in the production of the active metabolite of clopidogrel have been identified as CYP2C19, CYP3A4, and paraoxonase-1 (Clarke and Waskell, 2003; Bouman et al, 2011), although clopidogrel itself is a potent inhibitor of CYP2C19 and CYP3A4 (Richter et al, 2004). In general, patients that carry one or two CYP2C19 loss-of-function alleles exhibit diminished platelet inhibition after clopidogrel treatment compared to those with the EM genotype (Hulot et al, 2006; Brandt et al, 2007; Mega et al, 2009; Kubica et al, 2011).…”

“…Because the DNA sequence of CYP2C19 is highly polymorphic, this may account for much of the variability in the pharmacokinetics of drugs metabolized by CYP2C19. CYP2C19 metabolizes a number of drugs, including the antiulcer drug omeprazole (Andersson et al, 1992), the antiplatelet drug clopidogrel (Mills et al, 1992), the anticonvulsant mephenytoin (Andersson et al, 1992; Bertilsson, 1995), the antimalarial drug proguanil (Helsby et al, 1991; Ward et al, 1991), the anxiolytic drug diazepam (Bertilsson, 1995; Wan et al, 1996; Qin et al, 1999), and certain antidepressants such as citalopram (Sindrup et al, 1993), imipramine (Skjelbo et al, 1991), amitriptyline (Bouman et al, 2011), and clomipramine (Nielsen et al, 1994). The phenotype of CYP2C19 metabolic capacity can be categorized based on genotypes and includes extensive metabolizers (EM, two wild-type functional alleles), intermediate metabolizers (IM, two reduced functional alleles or one null allele and a functional allele), and poor metabolizers (PM, two non-functional alleles) of drugs.…”

Accreditation Standards for Pharmacy Courses in Australia: How Do We Stack Up?

“…14 So it seems that the experts are unable to completely dismiss the clopidogrel PON1 story or agree on the major determinant(s) of clopidogrel efficacy. [7][8][9][10][11][12][13] This shows why pharmacogenomics is so difficult for clinicians to warm to. How can clopidogrel, a pin-up of the pharmacogenomic cause, 15 still be causing such headaches?…”