Introduction,History,Target drugs,Future discussion

3. What is pharmacogenomics?
 Pharmacogenomics is the study of how an individual's genetic
inheritance affects the body's response to drugs.
 The term ‘Pharmacogenomics’ comes from the words
‘pharmacology’ (the science of drugs) and ‘genomics’ (the study of
genes and their functions) and is thus the intersection of
pharmaceuticals and genetics.
+
Shahid Chamran university of Ahvaz

4. personalized and Pharmacogenomics
• Pharmacogenetics- is often a study of the
variations in a targeted gene, or group of
functionally related genes.
• Pharmacogenomics , on the other hand is a
much broader investigation of genetic
variations at the level of the genome
Pharmacogenomics includes Pharmacogenetics

6. Factors involved in inter individual variation in
drug response

7. INTRODUCTION TO PHARMACOGENOMICS
The goal of pharmacogenomics is to:
• understand polymorphisms of drug
metabolizing enzymes
• transporters, and/or receptors that ultimately
determine the outcome of drug therapy.
Shahid Chamran university of Ahvaz

8. INTRODUCTION TO PHARMACOGENOMICS
Differences in drug response in
patients:
• Genetic (genotype, gender, ethnic
background)
• Environment (disease, previous
treatment and the environment)

9. INTRODUCTION TO PHARMACOGENOMICS
Focus:
At the beginning: On individual differences
But Over time: Genetic differences between
populations
pharmacogenomics is used For all organisms that are
able to respond to drugs or other chemicals
Shahid Chamran university of Ahvaz

10. INTRODUCTION TO PHARMACOGENOMICS
Research in the field of pharmacogenetics is moving in two main
directions:
• 1) identify specific genes and their products that are
associated with different diseases and may be targets for new
treatments.
• 2) Identification of genes and allelic variants of genes that
may affect the response to drugs for diseases.

11. History of pharmacogenetics
First discovered of Pharmacogenetics
was over 50 years ago.
A person with a genetic polymorphism
leads to deficiency G6PD
The time needed to Treatment with
primaquine
Hemolysis

12. History of pharmacogenetics
• Pythagoras510 BC(Some people eat fava anemia)
• Fredrich Vogel Word of pharmacogenetics(at first In 1959)
• Sir Archibald Garrod The role of genetics in response to
drugs(1990)
• In 1990, the emergence and development of the field was
divided into four periods:
The first stage (1910-1850)
The second stage (1950-1910)
The third stage (1990-1950)
The fourth stage (1990 and thereafter)

13. History of pharmacogenetics
The first stage(1910-1850)
With the discovery of three findings :
 The ability of the body's metabolism of foreign substances
(chemists and physiologists)
 Mendelian inheritance (Gregory Mendel)
 and drug receptors (Ehrlich)
Sir Archibald Garrod Said:
Errors of metabolism and chromosome in human and therefore
specific and personal biochemistry in each person is hereditary.

14. History of pharmacogenetics
The second stage (1950-1910) it seems to me, the most important
step
 Archibald Garrod, William Bateson ,Lucien Cuenot  genetic material has
an important role in the transfer of chemicals and chemical changes.
 Marshal(1918)  Blacks are more than resistant whites, against the
mustard gas
 Chen & middleton  Changes of ephedrine, and cocaine in the expansion
of eyes in white, black and Chinese are different.
 1920s  Differences in perceptions and emotions were discovered.
 Synder(1932)  Deficiency of taste is an inherited
 Alcohol dehydrogenase and aldehyde dehydrogenase deficiency Was
discovered.

15. History of pharmacogenetics
 N- acetyltransferase polymorphism  Racial distribution and depends on
the latitude of countries.
 Finally, double-stranded helix structure of DNA was discovered.
 Polymorphism discovery in hemoglobin  Sickle cell disease
 the SNP of: HFE gene  hemochromatosis
 Apolipoprotein E=ApoE  Cardiovascular and Alzheimer's disease,
 Factor’s gene 5 and protrombin gene  thrombosis
 Methylene Tetra Hydro Folate Reductase=MTHFR)  Venous
thromboembolism
Start correct and systematic pharmacogenetics.
thus

16. History of pharmacogenetics
The third stage (1990-1950) and The fourth stage (1990 and
thereafter)
• In 1956  the human chromosomes were observed.
• Chronic myelogenous Leukemia(CML)  Its association with chromosomal
defects (Philadelphia chromosome)
• Advances in technology
• The inheritance pattern of responses to some of the drugs were found
during this period.
• Until 1990, about100 of properties polymorphic and monomorphic
pharmacogenetics were identified.

17. There is a great deal of variability at the DNA level
between individuals that governs many characteristics
of the person, including his or her ability to respond to
a particular drug therapy:
 SNPs account for over 90% of the genetic variations
in the human genome.
 deletions,
 tandem repeats,
 and microsatellites
Genetics and metabolism of drugs

18. Single-nucleotide polymorphisms(SNPs) effect on
Pharmacogenomics :
 Single Nucleotide Polymorphism (SNP):
GAATTTAAG
GAATTCAAG
 SNPs are defined as Single base-pair positions
in genomic DNA that vary among individuals
in one or several populations.
 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.
 SNPs are used as genomic biomarkers.
 Hence SNP analysis can be used to enhance
drug discovery and development.
DNA molecule 1 differs from DNA
molecule 2 at a single base-pair
location (a C/T polymorphism)
Shahid Chamran university of Ahvaz

19. Clinical trials and the creation of an SNP linkage
disequilibrium database for a fictitious drug
Shahid Chamran university of Ahvaz

20. Genetics and metabolism of drugs
 Based on the response to a drug, individuals can be classified
as poor or extensive metabolizers.
 Molecular genetic testing can characterize an enzyme’s gene
to demonstrate which alleles (genetic polymorphisms) are
present, and how such alleles may affect enzymatic activity.
 Some of these alleles may be associated with loss or
reduction of gene function (alleles are denoted by an asterisk
(*) and a number). In general, *1 usually means a normally
functioning gene, and hence a normally functioning enzyme.

21. Different metabolizers of a drug that depend
on genetic makeup include:
 Extensive Metabolizers (EM): Individuals who have two
normal genes metabolize a drug normally.
 Poor Metabolizers (PM): Individuals with two non-functional
genes metabolize a drug very slowly compared to a normal
individual (EM).
 Ultra-Rapid Metabolizers (UM): These individuals may have
multiple copies of active genes and may metabolize a particular
drug so fast that the drug doesn’t have any pharmacological
effect.
 Intermediate Metabolizers (IM): These individuals may have
one active and one non-active allele for the same gene.

22. Enzymes involved in drug metabolism

23. Genetics and metabolism of drugs
Shahid Chamran university of Ahvaz

24. Drug target
There are three types of genetic variety:
 Some cases which play a role in the transmission,
distribution and elimination of external factors.
 Those that cause adverse drug reactions in the
body.
 And genetic variation which are targets of a drug.

25. DRUG
TARGETS
DRUG
METABOLIZING
ENZYMES
DRUG
TRANSPORTERS
PHARMACOKINETICSPHARMACODYNAMICS
Variability in
Efficacy/Toxicity

26. Drug target
Genetic variants in response to therapeutic
agents:
 Enzymes which play a role in drug
metabolism
 A drug targets proteins (transmitter and
receiver drug or drug carriers).

27. POLYMORPHISM OF ENZYMES RESPONSIBLE FOR DRUG
METABOLISM
 Most drugs undergo phase I metabolism, which involves oxidation,
reduction, or hydrolysis. Such reactions transform the drug into a more
polar water-soluble metabolite.
 some drugs can undergo phase II metabolism, which entails conjugation of
a polar group to the drug molecule to make it more polar.
 Enzymes responsible for such transformations may show a wide variation
in enzymatic activities due to genetic polymorphisms.
 The goal of pharmacogenomics is to understand such genetic
variations in order to predict the response of a particular
drug in a particular patient.

28. POLYMORPHISM OF ENZYMES RESPONSIBLE
FOR DRUG METABOLISM
 The cytochrome P-450 mixed-function oxidase (CYP)
 are N-acetyltransferase (NAT1 and NAT2)
 thiopurine-S-methyltransferase (TPMT)
 polymorphism of uridine-5 diphosphate glucuronyl
transferase (UDP-glucuronyl transferase)

29. Effect of Cytochrome P450 Enzymes on Drug Metabolism:
 The cytochrome P-450 mixed-function oxidase (CYP), the most important
family of enzymes responsible for drug metabolism, comprises a large
group of heme-containing enzymes.
 These enzymes are found in abundance in the liver and other organs.
 The major CYP isoforms responsible for the metabolism of drugs include
CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4/CYP3A5.

30. Effect of Cytochrome P450 Enzymes on Drug Metabolism:
 Cytochrome P450 enzymes are essential for the
metabolism of many medications.
 The most significant enzymes are : CYP3A4 and
CYP2D6.
Shahid Chamran university of Ahvaz

31. Enzymes involved in Pharmacogenomics:
 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

32. An example of different CYP2D6 alleles and their
effects on enzyme function

33. Key points regarding CYP enzymes:
 CYP3A4 is the predominant isoform of the CYP family
(almost 30%), and is responsible for the metabolism of
many drugs.
 Genetic polymorphisms of CYP2D6, CYP2C9, and
CYP2C19 have been well studied and account for some
wide interindividual responses to various drugs.
If the enzymatic activity is lost or significantly reduced due
to a genetic polymorphism, then the individual may not be
able to metabolize a particular drug (that is typically
metabolized through that enzyme) effectively, and can suffer
from drug toxicity.

34. Other polymorphically expressed drug-metabolizing enzymes
 a polymorphism of uridine-5 diphosphate glucuronyl transferase (UDP-
glucuronyl transferase) may also play a vital role in metabolism of certain
drugs (e.g. irinotecan, an anticancer drug).
 This enzyme is responsible for conjugation of glucuronic acid with the drug
molecule in phase II metabolism, thus inactivating the drug.
 This enzyme is mostly found in the liver, but may also be present in other
organs.
 There are two main families of UDP-glucuronyl transferase: UGT1 and
UGT2.
 Polymorphisms of UGT1A1 and UGT2B7 play important roles in the phase
II metabolism of certain drugs.

35. Other polymorphically expressed drug-metabolizing enzymes
 N-acetyltransferase (NAT1 and NAT2) and thiopurine-S-methyltransferase
(TPMT).
 The slow acetylator phenotype of the NAT1/2 polymorphism results in
isoniazid-induced peripheral neuropathy and sulfonamide-induced hyper-
sensitivity reactions
 while TPMT catalyzes inactivation of various anticancer and anti-
inflammatory drugs.

36. Polymorphisms of the transporter and
receptor proteins:
 Most drug responses  Interaction of several
gene products that affect the pharmacokinetics
and pharmacodynamics.
 Today 500 to 1200 genes of drug transporter have
been identified
 The best example of a drug transporter:
 multidrug-resistant transporter
 and p-glycol- protine /MDR1

37. AmpliChip CYP450Using FDA-approved test
kit
• Determine the genotype of the patient
in terms of two CYPP450 enzymes: 2D6
and 2C19
• FDA approved the test on December 24,
2004. The AmpliChip CYP450 test is the
first FDA approved pharmacogenetic
test.
Pharmacogeneticstestingmethods

38. Pharmacogenetics testing methods
 Technologies and methods that used in pharmacogenetics:
1. The DNA microarray
2 -pyro-sequencing
3. Mass Spectrometry
4-Fluorescence based-platform
5-RFLP and RTPCR and their types (such as PCR-5 QPCR)

39. Pharmacogenetics and clinical application
 pharmacogenomics is one of the main members of
Individual therapy.
 Recipients of treatment with:
o Warfarin
o Chemotherapy by Specific anticancer drugs
o Pain management with certain opioids

40. Examples of drugs where pharmacogenomics testing is useful are
listed in this Table
Shahid Chamran university of Ahvaz

41. Pharmacogenetics and clinical application
 Pharmacogenetics in oncology:
Pharmacogenetics focused on the effects of genetics in cancer
treatment.
 Pharmacogenetics And selection of anticancer drugs:
• Thiopurine
• Irinotecan،
• Tamoxifen

42.  Thiopurine such as :
 6-mercaptopurine (6-MP)
 thioguanine
 and azathioprine (TPMT)
 Metabolized by: thiopurine-S-methyl transferase (TPMT)
Pharmacogenetics and clinical application

43. Metabolism of 6-mercaptopurin to 6-methylmercaptopurin by the
methylator TPMT.

44. Various alleles of the gene TPMT and their SNPs.

46. Irinotecan
 Irinotecan
7-ethyl-10- hydroxycamptothecin (SN-38)
(UGT1A1) UDP- glucuronosyl transferase
Active
metab
olite
Deto
xifica
tion

47. Irinotecan

48.  Tamoxifen (estrogen receptor-positive breast
cancer)
 Tamoxifen is a prodrug
 endoxifen (4-hydroxy-N-desmethyl-tomoxifer)
Tamoxifen
By CYP2D6

49. Pharmacogenetics in Cardiovascular Disease
Shahid Chamran university of Ahvaz
• Current Status of Pharmacogenetics in
Antithrombotic Drug Therapy:
• The impact of VKORC1 and CYP2C9
variants on warfarin response, established
the value of genetic variability to predict
the appropriate warfarin dose for
improving and easing the transition to a
therapeutic INR level.

50. Pharmacogenetics in Cardiovascular Disease
Pharmacogenetics and warfarin treatment
• Respond differently to warfarin dose:
 CYP2C9 genetic polymorphisms
 Vitamin K epoxide reductase complex (VKORC1)
 Patients with CYP2C9 * 2 and CYP2C9 * 3 alleles  Need
lower maintenance dose of warfarin

51. Warfarin consists of a racemic mixture of two
active enantiomers—R and S- forms
Shahid Chamran university of Ahvaz

52.  Antiplatelet drug Clopidogrel
Pharmacogenetics in Cardiovascular Disease

55. Drugs used for pain management, such as:
 Codeine , Dihydrocodeine, Fentanyl ,Hydrocodone
Methadone ,Morphine ,Oxycodone ,Tramadol, Tricyclic
antidepressante
• Metabolized By :
• polymorphic CYP450 enzymes such as:CYP2D6 and
CYP3A4
• And UGT2B7(uridine diphosphate glucuronyl transferase 2B7)
Pharmacogenetics in Selection of opioids

56. Shahid Chamran university of Ahvaz
• ultra-metabolizers  Multiple copies of
the gene CYP2D6
• extensive-metabolizer  With a single
copy of the wild type gene of CYP2D6
• intermediate metabolizers  Decrease in
enzyme activity
• poor metabolizers  any activity

57. The metabolic pathway of codeine in the body

58. The metabolism of codeine to morphine by CYP2D6
Shahid Chamran university of Ahvaz

59. The tricyclic antidepressant amitriptyline is
metabolized by CYP2C19 to the active metabolite
nortriptyline.
CYP2D6 is needed for deactivation of
nortriptyline.
Adverse drug reactions tend to be associated with
nortriptyline concentrations,
And poor metabolizers of CYP2D6 are more likely
to suffer from adverse effects due to the build-up
of nortriptyline concentrations.
Pharmacogenetics in Selection Psychoactive drugs

60. Pharmacogenetics in other miscellaneous drugs
• Organ transplant recipients receive immunosuppressants in
order to prevent organ rejection.
• These drugs are metabolized by the cytochrome P-450 family
of enzymes, including CYP3A4 and CYP3A5.
• Although polymorphisms of CYP3A4 do not alter the enzyme
activity significantly,
• polymorphisms of CYP3A5 may be clinically more significant
because enzyme activities can vary significantly between
different alleles.

61. Pharmacogenetics in other miscellaneous drugs
• Pharmacogenomics testing can be used to identify
polymorphisms of CYP3A5 to predict optimal initial dosage of
Tacrolimus.
• HLA-B*1502, which is more abundant among Asians, is
associated with severe skin rashes (including Stevens Johnson
syndrome) following treatment with carbamazepine.
• HLA-B*5701 is strongly associated with hypersensitivity
towards the anti-HIV drug abacavir.
• HLA-B*5801 is associated with hypersensitivity to allopurinol

62. Shahid Chamran university of Ahvaz
1. Preparing profiles related to sensitivity of the
pharmaceutical, food and other external factors.
2. Preparing profiles of the SNP.
3. Create profiles of diagnostic markers and
laboratory tests
4. Determination of the location of the cell and
function of proteins and metabolic pathways in
different cell lines.
Necessary action to Advancement of
pharmacogenetics in the future

63. Shahid Chamran university of Ahvaz
5. Preparing profiles of ethnic diversity and racial.
6. The appropriate design of drugs
7. Comparison profiles between the genomes of
different organisms
Necessary action to Advancement of
pharmacogenetics in the future

65. Necessary conditions for stratified medicine.

66. Therapeutic continuum: empirical, stratified, and
personalized medicines

68. Pharmacogenetic tests validated in clinical studies and
recommended in the drug labels are detailed in table 1.

69. Irinotecan
CAMPTOSAR®
CRC
UGT1A1
First FDA approved pharmacogenetic test ““Third Wave Technologies, Invader
assay”” (2005), with dose optimization guidelines dependent on UGT1A1 genotype:
avoid severe (grade III/IV) neutropenia and diarrhoea for those who are at high risk,
i.e. Homozygous (and possibly heterozygous) for UGT1A1*28 and UGT1A1*1 alleles.
Warfarin
COUMADIN®
Thrombo-embolism
CYP2C9 and
VKORC1
(-1639G>A)
Improve drug efficacy and safety: avoid increased risk of bleeding to patients
homozygous or heterozygous for CYP2C9*2 or CYP2C9*3 alleles by prescribing
differentiated doses (as compared with those for CYP2C9*1 homozygous).
Pharmacogenetic test: ““Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test;
therapeutic algorithm based on genotype and clinical factors
(http://www.WarfarinDosing.org.)
Clopidogrel
(prodrug)
PLAVIX®
Thrombo-embolism
CYP2C19
Improve efficacy and safety: doses adjustment for ultrarapid metabolizers who are
carriers of CYP2C19*17/*17 genotype and for poor metabolizers due to CYP2C19*2
allele presence.
Carbamazepine
TEGRETOL®
Epilepsy
HLA-B*1502
allele
Improve drug safety: avoid serious dermatologic reactions (Stevens––Johnson
syndrome and/or toxic epidermal necrolysis).
Drug
Indication
Pharmacogenetic
biomarker Comments
Rasburicase
ELITEK®
Hyperuricemia G6PD
Improve drug safety: pre-therapy screening to avoid severe hemolytic reactions
associated with G6PD deficiency.

70. Clozapine CLOZARIL®
Schizophrenia HLA-DQB1
Improved safety: pharmacogenetic testing, in parallel with WBC monitoring, avoid
prescription to patients with high agranulocytosis risk.
Test „„PGxPredict: Clozapine””
Tretinoin VESANOID® APL PML/RARD Improve drug efficacy and safety.
Disease confirmation by t(15;17) cytogenetic marker
Valproic acid
DEPAKENE®
Seizures
UCD deficiency
Confirm disease: consider evaluation of UCD before therapy with valproate
Only informational pharmacogenetic tests in drug label
Panitumumab
VECTIBIX®
Cetuximab
ERBITUX® mCRC
K-RAS Improve efficacy: clinical benefit limited to patients with nonmutated K-RAS.
Imatinib
GLEEVEC®
GIST
C-KIT
Improve drug efficacy: clinical benefit in patients carriers of the activating C-KIT
mutation
Busulfan
MYLERAN®
CML
Philadelphia chromosome Improve drug efficacy: responders are positives for Philadelphia chromosome (BCR-
ABL)
Capecitabine
XELODA®
CRC
DPD deficiency
Improve drug safety: decreased DPD and increased level of 5fluorouracil is associated
with severe toxicity (e.g., stomatitis, diarrhoea, neutropenia and neurotoxicity).
Primaquine Malaria G6PD
deficiency
Improve drug safety: avoid acute intravascular hemolytic reactions.
Isoniazid,
Pyrazinamide
TB
NAT
Improve drug safety: dose adjustements based on NATmetabolic status, for slow
acetylators and fast acetylators to avoid severe adverse reaction of peripheral
neuropathy, or lack of efficacy, respectively.
Erlotinib
TARCEVA® NSCLC EGFR mutations
Confirm disease (at least 10% of the cells are EGFR-positive) and response to EGFR
tyrosine kinase inhibitors
Lenalidomide
REVLIMID®
Myelodysplasic syndromes
Deletion of chromosome
5q
(del[5q])
Confirm disease: indicated to treat those with transfusion dependent anemia caused
by low- or intermediate-risk of myelodysplasic syndromes associated with 5q(del[5q])

71. 72
ShahidchamranuniversityofAhvaz
Department of Genetics, Harvard University
Genetics is not perceived simply as a subject, but
rather as a way of viewing and approaching biological
phenomena.