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Clinical Implications of Pharmacogenetics
Application of CYP450 Genotyping in Clinical Practice
The polymorphic nature of the CYP450 genes, which greatly affects individual drug
response and adverse reactions, includes CNVs, missense mutations, insertions and
deletions, and mutations affecting gene expression and activity of mainly CYP2A6,
CYP2B6, CYP2C9, CYP2C19 and CYP2D6, which have been extensively studied
and well characterized. CYP1A2 and CYP3A4 expression varies signifi cantly, and
the cause has been suggested to be mainly of genetic origin but the exact molecular
basis remains unknown. This variability is of greatest importance for treatment with
several antidepressants, antipsychotics, antiulcer drugs, anti-HIV drugs, anticoagu-
lants, antidiabetics and the anticancer drug tamoxifen. Pharmacoepigenetics shows
how gene methylation infl uences the expression of CYP. In addition microRNA
(miRNA) regulation of P450 has been described. A review has concluded that the
pharmacogenetic knowledge regarding CYP polymorphism now developed to a
stage where it can be implemented in drug development and in clinical routine for
specifi c drug treatments, thereby improving the drug response and reducing costs
for drug treatment (Ingelman-Sundberg et al. 2007 ).
Pharmacogenomic Biomarker Information in Drug Labels
A review of 1,200 drug labels of FDA-approved drugs in the US from 1945 to 2005
revealed that 121 contained pharmacogenomic information: 69 referred to human
genomic biomarkers, and 52 referred to microbial genomic biomarkers. Of the
labels referring to human biomarkers, 43 (62 %) pertained to polymorphisms in
cytochrome P450 enzyme metabolism, with CYP2D6 being most common. Of 36.1
million patients whose prescriptions were processed by a large pharmacy benefi ts
manager in 2006, about 8.8 million, i.e., approximately one fourth, received one or
more drugs with human genomic biomarker information in the drug label (Frueh
et al. 2008 ). The study concluded that incorporation and appropriate use of pharma-
cogenomic information in drug labels should be tested for its ability to improve
drug use and safety in the US. Currently, there are labels for >141 FDA-approved
drugs that contain proper pharmacogenomic biomarker information (see Table 4.9 ).
There is a need for increasing this number.
Genotype-Based Drug Dose Adjustment
Genotype-based drug dose adjustment information can be useful when the drug is
introduced into clinical practice and would enable the dose adjustment for individu-
alized therapy. Genetically determined interpatient variability or variations in
4 Pharmacogenetics