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expression in some of the polymorphic enzymes are of interest to the practicing
physicians. The clinical signifi cance of genetic polymorphisms and other genetic
factors may be related to substrate, metabolite, or the major elimination pathway.
Genetic polymorphism has been linked to three classes of phenotypes based on the
extent of drug metabolism.
- Effi cient metabolism (EM) is characteristic of normal population.
- Poor metabolism (PM) is associated with accumulation of specifi c drug sub-
strates and is typically an autosomal recessive trait requiring mutation or deletion
of both alleles for phenotypic expression. - Ultrarapid metabolism (UM) results in increased drug metabolism and is an
autosomal dominant trait arising from gene amplifi cation.
Many selective serotonin reuptake inhibitors interact with CYP2D6 enzyme. The
most notable example of this is fl uoxetine. Through competition with CYP2D6 sub-
strates, these drugs precipitate a drug-induced poor metabolism phenotype. It is
likely that effects of CYP2D6 inhibitors on the metabolism of CYP2D6 substrates
would be more pronounced in heterozygous extensive metabolism. This, however,
has not been proven as yet. Clinical signifi cance of CYP2C19 polymorphism has
not yet been fully investigated as yet. Considering the relative abundance of this
enzyme and the signifi cant number of pharmaceutical substrates, clinical signifi -
cance is likely to be signifi cant.
Table 4.9 (continued)Drug Therapeutic area Gene Referenced subgroup
Valproic Acid (2) Neurology NAGS, CPS1,
ASS1, OTC,
ASL, ABL2
Urea cycle enzyme
defi cientVelaglucerase Alfa Metabolic disorders GBA Lysosomal
glucocerebrosidase
enzyme
Vemurafenib Oncology BRAF BRAF V600E mutation
positive
Venlafaxine Psychiatry CYP2D6 CYP2D6 poor metabolizers
Voriconazole Infectious diseases CYP2C19 CYP219 intermediate or
poor metabolizers
Warfarin (1) Cardiology or
Hematology
CYP2C9 CYP2C9 intermediate or
poor metabolizers
Warfarin (2) Cardiology or
Hematology
VKORC1 VKORC1 rs9923231 A
allele carriers
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4 Pharmacogenetics