Biomedical Engineering Reference
In-Depth Information
Table 1
Relevant pharmacogenomic drugs and possible phenotypic
assessments
Drug
Genotype target
Phenotype target
Warfarin
CYP 2C9 and VKORC1
a
Prothrombin time/INR
b
Azothioprine
TPMT
c
Red cell TPMT
Tamoxifen
CYP 2D6
Endoxifen
Clopidogrel
CYP 2C19
R-130964 metabolite
Platelet aggregometry
Codeine
CYP 2D6
Morphine
a
Vitamin K reductase epoxide complex
b
International normalized ratio
c
Thiopurine methyltransferase
“right person” at the “right time.” Pharmacogenomics is a science that predicts ther-
apeutic efficacy and toxicity avoidance by tailoring drug therapy according to an
individual's genetic makeup. Polymorphisms in the genes that encode the enzymes
necessary in the inter- and intracompartmental transportation, metabolism, and
excretion of therapeutic drugs can have a major effect on the performance of a drug
in clinical practice. Currently, genotyping for the family of cytochrome (CYP)
microsomal enzyme systems is important in identifying individuals as slow, inter-
mediate and ultrarapid metabolizers relative to the wild type. There are specific
cytochrome isoenzymes that are responsible for the majority of the drugs that are
detoxified by the liver. Homozygous subjects who are slow metabolizers produce
enzymes that are defective and have low enzyme activity. Homozygous intermedi-
ate metabolizers produce enzymes that have reduced function. Alternately, an inter-
mediate metabolizer could result from a heterozygous individual who has one
wild-type copy and one null gene. Ultrarapid metabolizers have more “gene dupli-
cations,” i.e., more than the usual two copies of the CYP enzyme.
An individual's germ line “genotype” is created at birth and remains largely
unchanged during life. The major advantage of genotyping is that a determination
can be made in the absence of the drug itself. However, while the coded protein is
defined by the genotype, an individual's “phenotype” is dependent on genetic and
nongenetic factors. The level of RNA expression for an individual can be variable in
the amount of protein produced, and greatly affect the individual's phenotype. It has
been known for many years that the expression of the CYP enzymes from the liver
can be enhanced or inhibited by the presence of other drugs. Thus, for clinical phar-
macogenomics, measurement of the concentration of the drug or its metabolites may
be a better reflection of its enzyme activity. A disadvantage of drug measurements is
that for an accurate assessment of concentrations, the individual must be regularly
taking the drug at the prescribed dosage, and be at pharmacologic steady state. During
the drug induction phase, this might expose the individual to unwarranted and unex-
pected side effects for some medications. For drugs with long half-lives, there may
be a significant delay in the assessment of efficacy by therapeutic drug monitoring
(TDM) levels. Clearly, the effective therapeutic management of many therapeutic
drugs today is a combination of genotypes with phenotypes. Table
1
lists some of the
drugs that warrant pharmacogenomic testing, and the relevant phenotypic targets.
