Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)
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186 Applying Pharmacogenomics in Therapeutics
Dabigatran is administered as a prodrug that is rapidly biotransformed after
absorption. Both dabigatran and rivaroxaban are substrates for the drug efflux
pump P-glycoprotein, coded by the ABCB1 gene; and dabigatran (but not rivaroxaban)
undergoes metabolism by CYP450 enzymes, predominantly CYP3A4 and
CYP2J2. 13–15 To date, no data regarding pharmacogenomic studies of these agents
have been published, and it is currently unknown whether genetic variants modulate
their effectiveness.
Most pharmacogenetic studies on heparin 16 have been related to heparin-induced
thrombocytopenia (HIT) and its thromboembolic complications. Recently, it has
been proposed that the PlA2 polymorphism of the GPIIIa gene may modulate the
pro-thrombotic effects of HIT. 17 However, data on this association are not consistent. 18
There are also controversial data regarding the association between platelet FcγRIIA
H131R and platelet factor 4 polymorphisms with HIT, 19–21 whereas the association of
hemostatic polymorphisms with thromboembolic complications is certainly weak. 18
It was shown that the homozygous 131Arg/Arg genotype resulted in significantly more
common HIT events. 20 However, other studies did not support this finding. 21 These
preliminary results demonstrated that more evidence is needed before the patient’s
genotype can be used for prevention of HIT events. 20,21
CLOPIDOGREL
Antiplatelet agents such as aspirin and ADP receptor antagonists are effective in
reducing recurrent ischemic events. Considerable interindividual variability in the
platelet inhibition obtained with these drugs has initiated a search for explanatory
mechanisms and ways to improve treatment. In recent years, numerous genetic polymorphisms
have been linked to reduced platelet inhibition and lack of clinical efficacy
of antiplatelet drugs, particularly clopidogrel and aspirin.
The mechanism of action of clopidogrel, a thienopyridine, is to inhibit platelet
function. This will result in the prevention of cardiovascular events in patients
with acute coronary syndrome (ACS). This prodrug when enzymatically modified
produces bioactive thiol metabolite (SR 26334). This metabolite irreversibly binds
to the platelet P2Y12 receptor, inhibiting ADP-mediated platelet aggregation.
Interpatient genetic variability affects the response to clinical outcomes of clopidogrel
therapy. 22
SNPs in certain genes involved in clopidogrel metabolism, transport, and signaling
could affect the pharmacokinetics and pharmacodynamics of clopidogrel, which
include CYP1A2, CYP2C19, CYP3A4, CYP3A5, P-glycoprotein (ABCB1), paraoxonase
1 (PON1), and P2Y12. Persuasive evidence suggests that genetic variability
in CYP2C19 affects the efficacy of clopidogrel and has a role in preventing cardiovascular
events. 22
CYP2C19 genetic variations comprise one-third of all patients with a loss-offunction
allele, resulting in reduced conversion of clopidogrel to its active metabolite,
leading to more cardiovascular events. 23 Genetic variation is commonly seen
in Asians. It is estimated that 50% of Asians have one loss-of-function allele in
CYP2C19, resulting in impaired bioactive conversion of clopidogrel to its active
metabolite. 24