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By: TASNEEM HAMADA
Intrinsic factors: age, gender,
race/ethnicity, disease states, organ
dysfunctions, and genetics
Physiological changes: pregnancy,
Extrinsic factors: smoking, diet,
being able to find out how a drug will
affect you before you take it.
receiving a medication that is
specifically tailored to treat your
disease, while minimizing your risk of
developing adverse effects.
Although a person's environment,
diet, and general state of health can
all influence how he or she responds
to medicines, another important factor
The study of genetic basis of drug
To determine what the right medicine
is for you, based on your own genes.
You receive better and safer drugs the
Your doctor provide you with a more
Improve disease screening.
5% of hospitalization
Experienced by 10% of the
700,000 deaths per year
estimated to be the 4th or 6th leading
cause of death in the US for the
49% of drugs causing ADRs are metabolized by
7-22% of other randomly selected drugs are
substrates for polymorphic enzymes
Polymorphisms occur in transporters, receptors,
and other therapeutic targets are also associated
with interindividual variability in drug response.
Variation in DNA sequence.
Frequency: <1% of population.
2 major types:
Indels (less frequent in coding
Synonymous SNP < nonsynonymous
SNP (NEGATIVE PRESSURE)
Sickle cell anemia
Crigler Najjar syndrome
Population specific eg. African
• Plasma protein
Cytochrome P450 Enzymes:
TPMT = Thiopurine S-Methyl
Low levels of P4502D6 & P4502C19
Minor P450 enzyme in human liver
Metabolizes ~30% of drugs
Low enzyme activity “poor metabolizers”
higher risk of drug
toxicity and drug interactions
In all ethnic groups with diff.
In certain population
2% – 19%
In poor metabolizers:
- Higher risks for toxic reactions
- Higher risks for drug interactions
(e.g., codeine and propranolol)
Propranolol (in part)
Imipramine (in part)
Clomipramine (in part)
Amitryptylline (in part)
2% - 3%
3% - 5%
The UGTs are a superfamily of phase
II conjugating enzymes
This superfamily is divided into two
families, UGT1 and UGT2, which are
further subdivided into the three
subfamilies, UGT1A, UGT2A, and
The UGT1A gene is located on chromosome 2q37
and codes for nine functional proteins (UGT1A1,
UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7,
UGT1A8, UGT1A9, and UGT1A10).
The UGT2 family is located on chromosome 4q13
and codes for eight functional proteins (UGT2A1,
UGT2B4, UGT2B7, UGT2B10, UGT2B11,
UGT2B15, UGT2B17, and UGT2B28).
The enzyme isoforms coded within the UGT1A
locus consist of four shared exons (exons 2-5) and
one unique exon (exon 1) that contains the
SNPs within the four shared exons are common to
all the enzymes, whereas those found in the
variable exon 1 and the upstream promoter
regions are unique to each UGT1A isoform.
there are more than 60 known polymorphisms
in the UGT1A1 gene, many of which have
The UGT1A1*28 polymorphism, which is an
insertion of extra (TA) repeat in the promoter,
is associated with enzyme activity inversely
related to repeat length.
This insertion polymorphism affects the TATA
box upstream of UGT1A1, which is
responsible for the binding of general
transcription factor IID, which plays an
important role in the initiation of transcription.
individuals homozygous for (TA)7, or
UGT1A1*28 have a 70% reduction in
UGT1A1 gene expression compared
with those possessing the (TA)6 allele.
The UGT1A1*28 allele is thought to
explain up to 40% of the variability in in
vitro enzyme activity of UGT1A1.
Homozygous UGT1A1*28 allele with
reduced enzyme activity in Caucasian:
Two additional alleles at this location
have been identified in persons of African
ancestry, (TA)5 (or UGT1A1*36) and (TA)8
Another common functional
polymorphism found in exon 1 of the
gene, denoted as UGT1A1*6, is found in
Asian populations and results in the
substitution of an arginine for a glycine.
The allelic frequency of UGT1A1*6 in
Asians is 18-23%,with a 40%
reduction in enzyme activity as
compared with the wild-type enzyme.
conjugated inactive metabolite.
SN-38 is associated with neutropenia and
Patients with homozygous UGT1A1*28
allele are at increased risk for ADRs
following the initiation of therapy due to
increased level of SN-38.
Recommend decrease the starting dose of
irinotecan by at least 1 dose level to avoid
cytotoxicity for homozygous UGT1A1*28
Crigler-Najjar syndrome (CNS) is a rare
autosomal recessive disorder of bilirubin
caused by alterations in the coding sequence
of UGT. This results in complete absence of
UGT or the presence of abnormal UGT with
reduced or no enzyme activity.
Type 1 Crigler-Najjar syndrome is associated
with an almost complete absence of the
enzyme, which results in very high levels of
unconjugated hyperbilirubinemia (up to 50
mg/dL) at birth. Lower levels of serum bilirubin
(up to 20 mg/dL)
Type 2 Crigler-Najjar syndrome (Arias
syndrome) is associated with markedly
depressed activity of hepatic UGT
Treatment with phenobarbital can induce the
expression of UGT in patients with type 2
Crigler-Najjar syndrome, with a decrease in the
serum bilirubin level of approximately 25%.
has Oxygen here
TPMT - Thiopurine
The active thiopurine metabolite, 6-TGN, can
eventually results in myelosuppresion, a dose
limiting factor for therapy.
TPMT- deficient metabolizers can have
increased level of 6-TGN and are at higher risk
for severe, sometimes fatal, myelosuppresion.
Each copy of the TPMT gene will
produce some TPMT enzyme. This
leads to three different groups of
enzyme activity levels (low/low,
low/high, and high/high or deficient,
intermediate, and normal).
About 1 in 300 Caucasians and
African-Americans are TPMTdeficient.
If these patients are given a
standard drug dose, they may suffer
severe hematopoietic toxicity.
Many are able to achieve the
desired therapeutic effect from a
dose that is one tenth of the
normal metabolizer (homozygous functional
alleles): 90% ………. Dominant
intermediate metabolizer (heterozygous
with one nonfunctional allele): 10% ……….
deficient metabolizer (homozygous
nonfunctional alleles): 0.3% ………. Recessive
phenotyping for TPMT variant alleles is
recommended before thiopurine therapy.
give 6-10% of the standard dose of
thiopurine and monitor CBC
usually start on full dose, but dose
reduction is recommended to avoid
TPMT*3A most common TMPT Low Activity Allele
In Asians, TPMT*3A is uncommon, and TPMT*3C
is the most common variant
Several institutions screen for TPMT genotype
before administering chemotherapy