Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
By: TASNEEM HAMADA


Intrinsic factors: age, gender,
race/ethnicity, disease states, organ
dysfunctions, and genetics



Physiological chan...


being able to find out how a drug will
affect you before you take it.



receiving a medication that is
specifically t...


Although a person's environment,
diet, and general state of health can
all influence how he or she responds
to medicine...









To determine what the right medicine
is for you, based on your own genes.
You receive better and safer drugs...
Caused

5% of hospitalization
Experienced by 10% of the
hospitalized patients
700,000 deaths per year
estimated to be ...


49% of drugs causing ADRs are metabolized by
polymorphic enzymes



7-22% of other randomly selected drugs are
substra...
Polymorphism:
 Variation in DNA sequence.
 Frequency: <1% of population.
 2 major types:
 SNP
 Indels (less frequent ...
Synonymous SNP < nonsynonymous
SNP (NEGATIVE PRESSURE)
 Cystic fibrosis
 Sickle cell anemia
 Crigler Najjar syndrome
 ...
GENETIC
POLYMORPHISMS
Pharmacokinetic
• Transporters
• Plasma protein
binding
• Metabolism

Pharmacodynamic
•Receptors
•Io...


Cytochrome P450 Enzymes:





UDP-Glucuronosyl Transferase:




CYP 2D6
CYP 2C19

UGT 1A1

TPMT = Thiopurine S-Met...
Low levels of P4502D6 & P4502C19
P4502C19

P4502D6
P4502E1

P4502C9
Other

P4502C8

P4501A2
P4503A4
P4502B6 P4502A6
•

Minor P450 enzyme in human liver

•

Metabolizes ~30% of drugs

•

Low enzyme activity “poor metabolizers”
 autosomal...
Debrisoquine
Amphetamine
Dexfenfluramine
Ouanoxan
Ondansetron
Beta Blockers
Propafenone
S-metoprolol
Propranolol
Timolol
A...
 Polymorphism:
Cosmopolitan


In all ethnic groups with diff.
frequencies

Population



specific

In certain popula...
Caucasians
5% -10%
African-Americans 6%
Africans
2% – 19%
Japanese
Chinese

0.5%
0.7%

In poor metabolizers:
- Higher risk...
Omperazole
Lansoprazole
Pantoprazole
S-mephenytoin
Hexobarbital
R-mephobarbital
Phenytoin
Diazepam
Citalopram

Warfarin
Pr...
Caucasians
Africans

2% - 3%
3% - 5%

Chinese
Koreans
Japanese

~14%
~14%
~20%


The UGTs are a superfamily of phase
II conjugating enzymes



This superfamily is divided into two
families, UGT1 and ...


The UGT1A gene is located on chromosome 2q37
and codes for nine functional proteins (UGT1A1,
UGT1A3, UGT1A4, UGT1A5, UG...


The enzyme isoforms coded within the UGT1A
locus consist of four shared exons (exons 2-5) and
one unique exon (exon 1) ...






there are more than 60 known polymorphisms
in the UGT1A1 gene, many of which have
functional consequences
The UGT...


individuals homozygous for (TA)7, or
UGT1A1*28 have a 70% reduction in
UGT1A1 gene expression compared
with those posse...


Two additional alleles at this location
have been identified in persons of African
ancestry, (TA)5 (or UGT1A1*36) and (...


The allelic frequency of UGT1A1*6 in
Asians is 18-23%,with a 40%
reduction in enzyme activity as
compared with the wild...
carboxylesterase



Irinotecan
(active)

SN-38
(UGT1A1)

conjugated inactive metabolite.


SN-38 is associated with neutropenia and
life-threatening diarrhea.



Patients with homozygous UGT1A1*28
allele are a...


Crigler-Najjar syndrome (CNS) is a rare
autosomal recessive disorder of bilirubin
metabolism.



caused by alterations...






Type 1 Crigler-Najjar syndrome is associated
with an almost complete absence of the
enzyme, which results in very...
Regular Guanine
has Oxygen here

S

Other
Enzymes

6-MP
DRUG

TGN (Thioguanine
nucleotide)
ACTIVE Form
Disrupts Cell
Divis...


The active thiopurine metabolite, 6-TGN, can
eventually results in myelosuppresion, a dose
limiting factor for therapy....


Each copy of the TPMT gene will
produce some TPMT enzyme. This
leads to three different groups of
enzyme activity level...


If these patients are given a
standard drug dose, they may suffer
severe hematopoietic toxicity.



Many are able to a...
 TPMT-

normal metabolizer (homozygous functional
alleles): 90% ………. Dominant

 TPMT-

intermediate metabolizer (heteroz...
 Predominantly

genotyping or
phenotyping for TPMT variant alleles is
recommended before thiopurine therapy.

 TPMT

de...


TPMT*3A most common TMPT Low Activity Allele
in Caucasians



In Asians, TPMT*3A is uncommon, and TPMT*3C
is the most ...
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics
Upcoming SlideShare
Loading in …5
×

Pharmacogenetics

  • Be the first to comment

Pharmacogenetics

  1. 1. By: TASNEEM HAMADA
  2. 2.  Intrinsic factors: age, gender, race/ethnicity, disease states, organ dysfunctions, and genetics  Physiological changes: pregnancy, lactation  Extrinsic factors: smoking, diet, concomitant medications
  3. 3.  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.
  4. 4.  Although a person's environment, diet, and general state of health can all influence how he or she responds to medicines, another important factor is genes. Pharmacogenetics: The study of genetic basis of drug response. 
  5. 5.      To determine what the right medicine is for you, based on your own genes. You receive better and safer drugs the first time. Your doctor provide you with a more appropriate dose. Improve disease screening. Prevent disease.
  6. 6. Caused 5% of hospitalization Experienced by 10% of the hospitalized patients 700,000 deaths per year estimated to be the 4th or 6th leading cause of death in the US for the hospitalized patients
  7. 7.  49% of drugs causing ADRs are metabolized by polymorphic enzymes  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.
  8. 8. Polymorphism:  Variation in DNA sequence.  Frequency: <1% of population.  2 major types:  SNP  Indels (less frequent in coding regions) 
  9. 9. Synonymous SNP < nonsynonymous SNP (NEGATIVE PRESSURE)  Cystic fibrosis  Sickle cell anemia  Crigler Najjar syndrome  Positive pressure:  adventageous polymorphism  Population specific eg. African Americans 
  10. 10. GENETIC POLYMORPHISMS Pharmacokinetic • Transporters • Plasma protein binding • Metabolism Pharmacodynamic •Receptors •Ion channels •Enzymes •Immune molecules 19
  11. 11.  Cytochrome P450 Enzymes:    UDP-Glucuronosyl Transferase:   CYP 2D6 CYP 2C19 UGT 1A1 TPMT = Thiopurine S-Methyl transferase
  12. 12. Low levels of P4502D6 & P4502C19 P4502C19 P4502D6 P4502E1 P4502C9 Other P4502C8 P4501A2 P4503A4 P4502B6 P4502A6
  13. 13. • Minor P450 enzyme in human liver • Metabolizes ~30% of drugs • Low enzyme activity “poor metabolizers”  autosomal recessive  higher risk of drug toxicity and drug interactions
  14. 14. Debrisoquine Amphetamine Dexfenfluramine Ouanoxan Ondansetron Beta Blockers Propafenone S-metoprolol Propranolol Timolol Alprenolol Bufuralol Carvedilol Antiarrhythmics Encainide Flecainide S-mexillitene Lidocaine Antipsychotics Perphenazine Thioridazine Haloperidol Risperidone Minaprine Antidepressants Venlafaxine Fluoxetine Analgesics Fluvoxamine Dextromethorphan Paroxetine Codeine Amitriptylline Tramadol Desipramine Clomipramine Imipramine
  15. 15.  Polymorphism: Cosmopolitan  In all ethnic groups with diff. frequencies Population   specific In certain population Lower frequency
  16. 16. Caucasians 5% -10% African-Americans 6% Africans 2% – 19% Japanese Chinese 0.5% 0.7% In poor metabolizers: - Higher risks for toxic reactions - Higher risks for drug interactions (e.g., codeine and propranolol)
  17. 17. Omperazole Lansoprazole Pantoprazole S-mephenytoin Hexobarbital R-mephobarbital Phenytoin Diazepam Citalopram Warfarin Proguanil Teniposide Nilutamide Indomethacin Moclobemide Propranolol (in part) Imipramine (in part) Clomipramine (in part) Amitryptylline (in part)
  18. 18. Caucasians Africans 2% - 3% 3% - 5% Chinese Koreans Japanese ~14% ~14% ~20%
  19. 19.  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 UGT2B.
  20. 20.  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).
  21. 21.  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 substrate-binding domain.  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.
  22. 22.    there are more than 60 known polymorphisms in the UGT1A1 gene, many of which have functional consequences 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.
  23. 23.  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:
  24. 24.  Two additional alleles at this location have been identified in persons of African ancestry, (TA)5 (or UGT1A1*36) and (TA)8 (or UGT1A1*37).  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.
  25. 25.  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.
  26. 26. carboxylesterase  Irinotecan (active) SN-38 (UGT1A1) conjugated inactive metabolite.
  27. 27.  SN-38 is associated with neutropenia and life-threatening diarrhea.  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 allele carriers.
  28. 28.  Crigler-Najjar syndrome (CNS) is a rare autosomal recessive disorder of bilirubin metabolism.  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.
  29. 29.    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%.
  30. 30. Regular Guanine has Oxygen here S Other Enzymes 6-MP DRUG TGN (Thioguanine nucleotide) ACTIVE Form Disrupts Cell Division TPMT - Thiopurine Methyltransferase 6-MP Drug INACTIVATED Cleared from Body
  31. 31.  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.
  32. 32.  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.
  33. 33.  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” dose.
  34. 34.  TPMT- normal metabolizer (homozygous functional alleles): 90% ………. Dominant  TPMT- intermediate metabolizer (heterozygous with one nonfunctional allele): 10% ………. Codominant  TPMT- deficient metabolizer (homozygous nonfunctional alleles): 0.3% ………. Recessive
  35. 35.  Predominantly genotyping or phenotyping for TPMT variant alleles is recommended before thiopurine therapy.  TPMT deficient metabolizers: give 6-10% of the standard dose of thiopurine and monitor CBC carefully.  TPMT intermediate metabolizers: usually start on full dose, but dose reduction is recommended to avoid toxicity.
  36. 36.  TPMT*3A most common TMPT Low Activity Allele in Caucasians  In Asians, TPMT*3A is uncommon, and TPMT*3C is the most common variant  Several institutions screen for TPMT genotype before administering chemotherapy

×