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paroxetine, increases in imipramine concentrations with fl uvoxamine, and increased
phenytoin concentrations with sertraline. Due to interindividual variability in drug
disposition, plasma concentrations of SSRIs vary signifi cantly among individuals.
Change in enzyme activity as a result of drug-drug interaction may be equally clini-
cally relevant for heterozygous extensive metabolizers (toward poor-metabolizer
status) and homozygous extensive metabolizers (toward heterozygous extensive-
metabolizer status). A possible cause of signifi cant interindividual differences in the
magnitude of CYP2D6 inhibition is the pharmacokinetic variability of the inhibitor
itself. Another determinant of overall interaction magnitude is unbound drug con-
centration in plasma and hepatocytes. A similar extent of intersubject variability in
hepatocyte drug concentration is likely at the site of enzyme inhibition.
There are positive and signifi cant correlations between paroxetine and fl uoxetine
concentrations and CYP2D6 inhibition. These correlations illustrate the role of
plasma concentrations and dosage on magnitude of enzyme inhibition. The poten-
tial of paroxetine, a CYP2D6 substrate, as an inhibitor may be further affected by
specifi c genotype and basal metabolic capacity of individual subjects.
Cytochrome P450 Polymorphisms and Response to Clopidogrel
Clopidogrel requires transformation into an active metabolite by cytochrome P450
(CYP) enzymes for its antiplatelet effect. A study has tested the association between
functional genetic variants in CYP genes, plasma concentrations of active drug
metabolite, and platelet inhibition in response to clopidogrel in healthy subjects
(Mega et al. 2009 ). The investigators then examined the association between these
genetic variants and cardiovascular outcomes in a separate cohort of subjects with
acute coronary syndromes who were treated with clopidogrel in the Trial to Assess
Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with
Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI). In healthy sub-
jects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-
function allele had a relative reduction of 32.4 % in plasma exposure to the active
metabolite of clopidogrel, as compared with noncarriers. Carriers also had an abso-
lute reduction in maximal platelet aggregation in response to clopidogrel that was
9 percentage points less than that seen in noncarriers. Among persons treated with
clopidogrel, carriers of a reduced-function CYP2C19 allele had signifi cantly lower
levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a
higher rate of major adverse cardiovascular events, including stent thrombosis, than
did noncarriers. In another study, among patients with an acute myocardial infarc-
tion who were receiving clopidogrel, those carrying CYP2C19 loss-of-function
alleles had a higher rate of subsequent cardiovascular events than those who were
not (Simon et al. 2009 ). This effect was particularly marked among the patients
undergoing percutaneous coronary intervention.
In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006–
2008), clopidogrel was administered for 7 days to 429 healthy Amish persons and
measured response by ex vivo platelet aggregometry (Shuldner et al. Shuldiner et al.
2009 ). A genome-wide association study was performed followed by genotyping
4 Pharmacogenetics