PHARMACOGENOMICS:

A New Basis for Drug

Therapy

Olufunsho AWODELE
Department of Pharmacology, Therapeutics &
Toxicology, University of Lagos
1
10/08/21
Definition(s)
Pharmacogenomics: Study of genomic influence on drug
response, often using high-throughput data (sequencing, SNP
chip, expression, proteomics - COMPLEX interactions)

Pharmacogenetics: Study of individual gene-drug interactions,

usually one or two genes that have dominant effect on a drug
response (SIMPLE relationship) Integration of
Molecular
The role of Biology,
genetics in Pharmacology,
drug Therapeutics,
responses Toxicology
2
Johnson, 2003; Squassina et al., 2010; Center for Pharmacogenomics and
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Individualized Therapy, 2014; Al-Eitan1 & Haddad, 2014

Background
The Human Genome Project (HGP)

Collaborative research program whose goal was the

complete mapping and understanding of all the genes of
human beings

Project started in 1984

Project completed in 2003

Revealed about 20,500 human genes

3
National Institute of Health, 2015 10/08/21
 Genetic Variation
A Key to Human Individuality
People are 99.9% identical
at the DNA level

But this still leaves

~3,000,000 specific DNA
differences between people

Such differences affect our

appearance, behavior,
susceptibility to disease and
response to medications
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National Institute of Health, 2015; Hughes et al.; 2015
 DeoxyriboNucleic Acid (DNA)

Purine (2-C)
Guanine(G),
Adenine(A),

Pyrimidine (1-C)
Cytosine (C)
Thymine(T)
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Mashaghi & Katan, 2013 10/08/21
The Central Dogma: DNARNAProtein
DNA: A long double-stranded string
of nucleotides that encode for many
genes.

Gene

RNA: A single-stranded copy

Codon 1Codon 2

Protein: Proteins are composed of Amino acid 1Amino acid 2

amino acids. Amino acids are made
from triplets of nucleotides called
codons.
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Protein!
A small change in the gene sequence can
result in a very different protein
DNA: ATG GTG CTG TCT CCT

Amino Acids/Protein: Met Val Leu Ser Pro

DNA: ATG GTG CTG TCT ACT

Amino Acids/Protein: Met Val Leu Ser Thr

Changes in DNA are called variations or mutations

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Variations in the DNA (genotype) can cause observable changes (phenotype)
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individuals
Typical Pharmacogenetic Traits
N-acetylase transferase (NAT 2) 45-65% Caucasians;
 Slow inactivation of isoniazid, dapsone 10-15% Africans

Serum Pseudocholinesterase
 Prolonged respiratory paralysis on exposure 1 in 2000 Caucasians

to suxamethonium

Glucose 6 Phosphate Dehydrogenase (G6PD)

1 in 100 African
 Hemolysis (anemia) from antimalarials American

Thiopurine methyl transferase (TPMT) 2% Low; 20%

Medium; 70% High
 Bone marrow toxicity from thiopurine, Expression 8
mercaptopurine
Swarbrick, 2005
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TPMT on 6MP

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Evans Nature Reviews Cancer (2006)
Modern Therapeutics
Requires adequate drug prescription, which implies

The Right Dose

The Right Drug

The Right Indication

The Right Patient

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Wang et al., 2011 10/08/21
Factors that determine drug response

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Adapted from: Lehne, 2007
CYP families in humans
Cytochrome P450 is a family of isozymes responsible for the
biotransformation of several drugs

Humans have 57 genes

Divided among 18 families of cytochrome P450

CYP1, CYP2, CYP3, CYP4, CYP5, CYP7, CYP8, CYP11,

CYP17, CYP19, CYP20, CYP21, CYP24, CYP26, CYP27,
CYP39, CYP46, CYP51

CYP2A6, CYP2B6, CYP2C9 ,CYP2C19, CYP2D6,

CYP2E1 and CYP3A4 are responsible for metabolizing most
clinically important drugs 12
Brutlag, 2011
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Family Function Members Names
Drug and steroid
(especially estrogen)
CYP1A1, CYP1A2,
CYP1 metabolism, 2 subfamilies, 3 genes,
CYP1B1
benzo(a)pyrene
toxification

CYP2A6, CYP2A7,
CYP2A13, CYP2B6,
CYP2C8, CYP2C9,
Drug and steroid 13 subfamilies, 16 CYP2C18, CYP2C19,
CYP2
metabolism genes, CYP2D6, CYP2E1,
CYP2F1, CYP2J2,
CYP2R1, CYP2S1,
CYP2U1, CYP2W1

Drug and steroid

CYP3A4, CYP3A5,
CYP3A7, CYP3A4313
CYP3 (including 1 subfamily, 4 genes,
testosterone) metab
Cytochrome P450 Nomenclature Committee, 2011
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CYP Enzymes in Metabolism of Some Clinically
Important Drugs
CYP Enzyme Examples of substrates
1A1 Caffeine, Testosterone, R-Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6 17-Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S-
Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin,
Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and R-
Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
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Rendic,2002
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Drug-CYP Interactions
Enzyme (CYP) Substrate Inhibitor Inducer
1A2 Clozapine, haloperidol Cimetidine Tobacco smoke
2B6 Bupropion Thiotepa Phenobarbital
2C19 Citalopram Fluoxetine Prednisone
2C9 Fluoxetine Paroxetine
Secobarbital
2D6 Most ADs, APs CPZ, ranitidine
Dexamethasone
2E1 Gas anesthetics Disulfiram Ethanol
3A4,5,7 Felodipine Grapefruit juice Glucocorticoid

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–http://www.georgetown.edu/departments/pharmacology/clinlist.html
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Effect of Grapefruit Juice on
Felodipine Plasma Concentration

5mg tablet
with juice

without

Cl
Cl

Cl
H Cl
CH 3 O 2 C CO 2 CH 3 3A4
CH 3 O 2 C CO 2 CH 3

CH 3 N CH 3
CH 3 N CH 3
H
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Bailey, et al.,1998
Risks associated with CYP enzyme inhibition or induction

Induction of CYP enzymes

Inhibition of CYP enzymes


Increased degradation
Decreased degradation
of co-medicated drugs
of co-medicated drugs


Decreased drug plasma
Increased drug plasma
concentrations
concentrations


Loss of pharmacological
Risk of severe
effect
adverse events

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Risk of therapeutic failure
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 CODEINE
&
TAMOXIFEN
METABOLISM
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Codeine and CYP2D6
Codeine is a commonly used opioid
codeine is a prodrug
it must be metabolized into morphine for activity

Cytochrome P450 allele CYP2D6 is the metabolizing enzyme

in the liver

7% of Caucasians are defficient in CYP2D6 gene

codeine does not work effectively in these individuals

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Codeine Metabolism

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Thorn, 2009
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Limitations
The Cost Factor and Access to Genomic Technologies

Concerns about the confidentiality of genetic information

 Employer could get the results of a genetic test that

showed whether you are more likely to get sick in
the future

 Health insurance company

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Conclusion
Genetic variants determine the pharmacological response to
drugs

Pharmacogenomics is expected to lead to:

Better and safer drugs
More accurate methods of determining appropriate drug
dosages

In the future, it is likely that the complete genetic profile for

individuals will be determined around the time of birth and
available as part of the persons electronic medical record for
appropriate drug therapy 22
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THANK YOU

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