Pharmacogenomics is the study of how an individual's genetic inheritance affects their body's response to drugs. Certain cytochrome P450 enzymes are involved in drug metabolism and can impact how drugs are absorbed, distributed, metabolized and excreted from the body. Single nucleotide polymorphisms (SNPs) in genes that encode these enzymes or drug targets can help explain inter-individual variability in drug responses. Pharmacogenomic testing may help optimize drug therapy for conditions like cancer, cardiovascular disease, and asthma by matching patients with medications based on their genetic profile.
2. What is pharmacogenomics?
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Pharmacogenomics is the study of how an individual's genetic inheritance affects the
body's response to drugs.
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The term âPharmacogenomicsâ comes from the words âpharmacologyâ (the science of
drugs) and âgenomicsâ (the study of genes and their functions) and is thus the
intersection of pharmaceuticals and genetics.
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3.
4. Enzymes involved in
Pharmacogenomics:
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Cytochrome P450 (CYP) family of enzymes is
involved in metabolism of several drugs.
Example:
CYP2D6 enzyme
CYP3A4 enzyme
CYP2A6enzyme
CYP2B6 enzyme
CYP2C9enzyme
CYP2C19enzyme
CYP2E1 enzyme
5. Effect of Cytochrome P450 Enzymes on
Drug Metabolism: are essential for the metabolism of
ï” Cytochrome P450 enzymes
many medications.
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The most significant enzymes are : CYP3A4 and CYP2D6.
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These enzymes are Haemoglobin containing mono-oxygenase and
are divided into 2 primary groups :
Steroidogenic and Xenobiotic
6. ï”
Steroidogenic and Xenobiotic
P450 Enzymes:
Steroidogenic P450 enzymes :
These enzymes are found in
prokaryotes and in eukaryotes.
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Xenobiotic P450 enzymes :
These enzymes are found in smooth
endoplasmic reticulum of eukaryotes.
Xenobiotic metabolism is the set
of metabolic pathways that modify the chemical
structure of xenobiotics, which are compounds foreign
to an organism's normal biochemistry, such as drugs and
poisons.
7. ADME property of drug on drug
metabolism:
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ADME: Absorption Distribution Metabolism Excretion.
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ADME describes the deposition of pharmaceutical compounds
within an organism.
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The 4 criteria(ADME) all influence the drug levels and kinetics of
drug exposure to the tissue and hence influence the performance
and pharmacological activity of the compound as a drug.
8. Absorption :
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Drug Absorption is the movement of drug from its site of administration into the
blood stream.
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Absorption critically determines the compound's bioavailability.
Sites of Drug Absorption :
For a compound to reach a tissue, it usually must be taken into
the bloodstream, often via mucous surfaces like the digestive
tract (intestinal absorption), before being taken up by the target cells.
9. Distribution
ï” The drug needs to be carried to its effector site via blood stream, from there the
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compound is distributed into muscles and organs.
Different Drug Distribution Patterns :
ï± Pattern1 : The drug remains largely within the vascular system such as heart,
arteries.
Example :- Dextran.
ï± Pattern2 : Low molecular water soluble compounds such as ethanol and few
sulphonamides becomes uniformly distributed throughout the body water.
Example :- Disprine.
ï± Pattern3 : A few drugs are concentrated specifically in one or more tissues that
may or may not be the site of action.
Example :- Iodine-Iodine is concentrated by the thyroid gland.
ï± Pattern4 : Most drug exhibit a non-uniform distribution in the body. It is the
combination of Pattern1, Pattern2 and Pattern3.
10. Metabolism :
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Cytochrome P450 enzymes are essential for the metabolism of many
medications. The most significant enzymes are : CYP3A4 and CYP2D6.
Sites of Drug Metabolism :
ï± At Organ level :
The liver is the primary organ of drug metabolism.
The lungs, kidney, intestine, skin and placenta can also
carry out drug metabolism.
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At Cellular level :
Most enzymes involved in drug metabolism are located
within the lipophilic membrane of smooth endoplasmic reticulum.
11. ï±
At Biochemical level :
1. Phase1 reaction : This refers to those which convert a drug to a
more polar compounds by introducing or unmasking polar functional group such
as OH, NH2 or SH. Some Phase1 product are not eliminated properly and hence
undergo to the Phase2 reaction.
2. Phase2 reaction : This reaction involves conjugation of newly
established polar group with endogenous compounds such as H2SO4, Acetic Acid
or Amino Acid(typically Glycine). Eg: Glucuronide formation is the most common
Phase2 reaction.
12. Elimination :
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The kidney is the most important organ for the excretion of drugs and their
metabolites.
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Some compounds are also excreted via bile, sweat and saliva.
Mechanism of Drug Elimination
:
ï± Renal Glomerular Filtration :
It permits the passage of most drug molecules but
restricts protein bound drugs. Example : Digoxin
ï± Renal Tubular Secretion :
The kidney can actively transport some drugs
against a concentration gradient, even if the drugs are protein bound.
13. ï±
Renal Tubular Reabsorption :
Many drugs are passively
reabsorbed in the distal renal tubules.
Reabsorption is influenced
by physiochemical factors.
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Biliary Excretion :
Many drugs and their
metabolites are passed into the small
intestine via bile and may undergo
enterohepatic cycle.
14. Single-nucleotide
polymorphisms(SNPs) effect on
Single Nucleotide Polymorphism (SNP):
Pharmacogenomics : GAATTTAAG
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GAATTCAAG
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SNPs are believed to underlie susceptibility to such
common diseases as cancer, diabetes, and heart
disease and to contribute to the traits that make
individuals unique.
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SNPs are used as genomic biomarkers.
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DNA molecule 1 differs from DNA
molecule 2 at a single base-pair
location (a C/T polymorphism)
SNPs are defined as Single base-pair positions in
genomic DNA that vary among individuals in one or
several populations.
Hence SNP analysis can be used to enhance drug
discovery and development.
15. Personalized
medicine : cancer, target: Her2 gene)
(breast
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Herceptin
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Erbitux
(colorectal cancer, target: EGFR)
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Tarceva
(lung cancer, target: EGFR)
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Strattera
(attention-deficit/hyperactivity disorder,
Metabolism: P4502D6)
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6-mercaptopurine(6-MP)
(leukemia, Metabolism: TPMT)
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Antivirals
(i.e. resistance based on form of HIV)
etc. and the list is growing rapidly ...
17. Applications of
Pharmacogenomics :
ï” Oncology :
Pharmacogenomics can be used to isolate and identify specific
chemotherapeutic agents that have limited toxic side effects to an individual, but still
attack and destroy the cancerous tumour.
Pharmacogenomics can be applied to individuals having
dihydropyrimidine dehydrogenase(DPD) deficiency.
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Cardiovascular disorders :
In cardiovascular disorders the main concern is response to drugs such as
warfarin, clopidogrel, beta-blockers and statins.
CYP2C9 enzyme is involved in warfarin metabolism.
The CYP2D6 enzyme is used to treat hypertension and drugs often
prescribed to control heart problems.
18. ï”
Neurology :
Pharmacogenomics can be used in the treatment of Alzheimerâs
disease.
Alzheimerâs disease has two forms â familial and sporadic.
Apolipoprotein E isoform 4 (ApoE-4) is a gene which is associated
with Alzheimerâs disease.
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Asthma :
Pharmacogenomics can be used in the treatment of Asthma.
Genotyping for individual pharmacogenomics responses may be useful
in establishing an anti-asthmatic therapy.
19. Bibliography
:
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Bioinformatics Methods and Applications (Genomics, Proteomics
and Drug Discovery) Book.
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www.google.com
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From Wikipedia, the free encuclopedia.
Thank YouâŠâŠ
