Pharmacogenetics

Dr, P Derakhshandeh, PhD

Pharmacogenetics
genetic variations in
drug response
Among normal subject :
maximum rate of reaction of
drug-metabolizing enzymes
often differ widely
drug elimination rates measured
in vivo vary by fourfold to more
than fortyfold
depending on the drug and
population studied

Numerous twin and family
studies have shown that
genetic factors are
mainly responsible for
these large interindividual
variations.
Pharmacogenetics
has clinical consequences and
biologic significance
?
the inherent capacity to clear a
drug may differ among patients
A patient with rapid metabolism
may require larger, more
frequent doses to achieve
therapeutic concentrations
a patient with slow metabolism
may need lower, less frequent
doses
to avoid toxicity, particularly
for drugs with a narrow margin
of safety.
Many environmental and
developmental factors can
interact with each other and
with genetic factors to
affect drug response
Genetic, environmental, and
developmental factors that can
interact, causing variations in
drug response among patients.




PHARMACOKINETIC VARIATION

Acetylation
In about 50% of the U.S.
population,drug inactivation
by hepatic N-acetyltransferase
Such persons (slow acetylators)
require a longer time to
metabolize drugs that are
acetylated
therefore they are more
susceptible to adverse effects
of such drugs (eg, peripheral
isoniazid,)

In the rest of the population,
acetylation is rapid
Compared with slow
acetylators, such persons
require larger or more frequent
doses of drugs that are
acetylated (eg, isoniazid)
to obtain the desired
therapeutic response
Oxidation
In about 5 to 10% of whites
in North America and
Europe
oxidative biotransformation
of debrisoquin is decreased
if such persons take
debrisoquin for hypertension
they are at increased risk
of toxicity
Aldehyde dehydrogenase-2
About 50% of Japanese, Chinese,
and other Asian populations
lack aldehyde dehydrogenase-2
an enzyme involved in ethanol
metabolism
In such persons, alcohol ingestion
results in marked elevations of
blood acetaldehyde
in adverse effects (eg, facial
flushing, increased heart rate,
muscle weakness)
Glucose-6-phosphate
dehydrogenase (G6PD) deficiency
G6PD is essential for RBC reduction
reactions
maintain cytoskeletal integrity.
10% of black males, are at increased
risk of developing hemolytic anemia
when given oxidant drugs, such as
antimalarials (eg, chloroquine,
pamaquine,primaquine), aspirin,
and vitamin K.
G6PD

it is located at the q28 locus
(Pai et al., 1980).
All X-linked genetic conditions,
such as G6PD deficiency, are
more likely to affect males
than females
to have over 400 variant alleles
Different populations have
different types of mutations,
but within a specific population,
common mutations are usually
shared.
For example, in Egypt there
exists only one type of allele,
called the "Mediterranean"
variant,

demographics of G6PD deficiency
most of the affected individuals
reside in Africa, the Middle East,
and Southeast Asia. African
Americans and some isolated tribes
in Africa and Southeast Asia
exhibit the highest frequency of
incidence for any given population
a defective enzyme can be found
in as many as one in four people
among these populations (Scriver et
al., 1995).
CLINICAL
ASPECTS OF G6PD
DEFICIENCY
red blood cell can no longer
transport oxygen effectively
throughout the body
hemolytic anemia arises
neonatal jaundice, abdominal and/or
back pain, dizziness, headache,
dyspnea (irregular breathing), and
palpitations (Cecil, 1992)
NEONATAL JAUNDICE

Neonatal jaundice is a yellowish
discoloration of the whites of the
eyes and skin
a direct result of insufficient
activity of the G6PD enzyme in the
liver
In some cases, the neonatal
jaundice is severe enough to cause
death or permanent neurologic
damage (Beutler, 1994).
HEMOLYTIC ANEMIA

An anemic response can be
induced in affected individuals
by certain oxidative drugs,
fava beans, or infections
(Beutler, 1994).
Death : if the hemolytic
episode is not properly treated
Glutathione synthetase deficiency
In patients with RBC glutathione
synthetase deficiency (much rarer
than G6PD deficiency)
oxidant drugs cause hemolytic
anemia
in hepatocytes are at increased
risk of liver damage if given
such drugs as acetaminophen.
Cytochrome P450s
a multigene family of enzymes
in the liver
for the metabolic elimination of most
of the drugs currently used in medicine
Individuals that are poor
metabolisers of the genes encoding
specific cytochrome P450s often have
mutations which have inactivated the
enzyme and severely compromised the
ability to metabolize the
drug of interest
CYP2D6
One example: the cytochrome
P450: CYP2D6
a highly polymorphic gene that
is inactive in about 6% of
Caucasians
Many drugs which are used for
the treatment of psychiatric,
neurological, and cardiovascular
disease are metabolized by the
product of this gene
CYP2D6
In one variant of the gene
tandem repeat causing
individuals to metabolize the
substrate so quickly that a
therapeutic effect cannot be
achieved by conventional doses.

CYP2D6
Also, individuals that are poor
metabolisers of CYP2D6 cannot
convert codeine to the
analgesic morphine and do not
achieve the desired effect.