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Pharmacogenetics: Improvement of Existing Drug Treatments. Zhou Yan-Qiong. Background :. Clinical genetics Cytogenetic Somatic Cell Genetics Biochmical genetics Molecular genetics Cancer genetics Population genetics Immunogenetics Pharmacogenetics Genetic toxicology

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Presentation Transcript
background
Background:
  • Clinical genetics
  • Cytogenetic
  • Somatic Cell Genetics
  • Biochmical genetics
  • Molecular genetics
  • Cancer genetics
  • Population genetics
  • Immunogenetics
  • Pharmacogenetics
  • Genetic toxicology
  • Developmental genetics
  • Behavior genetics
pharmacogenetics
PHARMACOGENETICS

The study of genetically controlled variations in drug response

i key concepts and terms
I. Key Concepts and Terms

Monogenic: due to allelic variation at a single

gene

Polygenic: due to variations at two or more

genes

Polymorphic: frequently occurring monogenic

variants occurring at a frequency

>1%

normal distribution
Normal Distribution

Frequency

Activity

slide7

GENETIC

POLYMORPHISMS

Pharmacokinetic

Pharmacodynamic

  • Receptors
  • Ion channels
  • Enzymes
  • Immune molecules
  • Transporters
  • Plasma protein binding
  • Metabolism
ii genetic polymorphisms in drug metabolizing enzymes
II. Genetic polymorphisms in drug metabolizing enzymes

From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286:487-491, 1999.

genetic polymorphisms in drug metabolizing enzymes
Genetic polymorphisms in drug metabolizing enzymes
  • 1. Polymorph of debrisoquine
  • extensive metabolizer——EM
  • poor metabolizer ——PM*>12.6
  • recessive transmission,autosomal
slide10

DRUGS WHOSE METABOLISM CO-SEGREGATES WITH DEBRISOQUINE

alprenolol amitriptyline bufuralol clomipramine

codeine desipramine encainide ethylmorphine

flecainide fluoxetine guanoxan imipramine

metoprolol nortriptyline paroxetine phenformin

propafenone propranolol

slide11

2. Polymorph of Mephenetoin:

  • EM
  • PM:recessive transmission,autosomal
  • racial diversify
slide12

3. Glucose-6-phosphate dehydrogenase activity

Effects >300 million worldwide

CYP

MPO

PGH Synthase

R-NH2

R-NOH

ERYTHROCYTE

O2

NADP+ or

GSSG(?)

NAD+

HgbFe+2

HMP Shunt

G-6-PD

Dependent

R-NOH

MetHgb

Reductase

NADPH

or GSH(?)

HgbFe+3

R-NO

NADH

GSH

Reactive

Oxygen

Splenic

Sequestration

Semi-mercaptal

SOD

Catalase

GSH Peroxidase

sulfinamide

Detoxification

Hemolytic

Anemia

R-NH2

slide13

Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia in Subjects with G6PD Deficiency

Acetanilide Nitrofurantoin Primaquine

Methylene Blue Sulfacetamide Nalidixic Acid

Naphthalene Sulfanilamide Sulfapyridine

Sulfamethoxazole

slide14

INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS

Ethnic GroupIncidence(%)

Ashkenazic Jews 0.4

Sephardic Jews

Kurds 53

Iraq 24

Persia 15

Cochin 10

Yemen 5

North Africa <4

Iranians 8

Greeks 0.7-3

slide15

INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS

Ethnic GroupIncidence(%)

Asiatics

Chinese 2

Filipinos 13

Indians-Parsees 16

Javanese 13

Micronesians <1

slide16

4. N-ACETYLTRANSFERASE ACTIVITY

Distribution of plasma isoniazid concentration in 483 subjects

after and oral dose. Reproduced from Evans DAP. Br Med J 2:485, 1960.

slide17

ETHNIC DIFFERENCES IN THE DISTRIBUTION OF ACETYLATOR PHENOTYPE

Population% Slow% Hetero Fast% Homo Fast

South Indians 59 35.6 5.4

Caucasians 58.6 35.9 5.5

Blacks 54.6 38.6 6.8

Eskimos 10.5 43.8 45.7

Japanese 12 45.3 42.7

Chinese 22 49.8 28.2

From: Kalo W. Clin Pharmacokinet 7:373-4000, 1982.

slide18

XENOBIOTICS SUBJECT TO POLYMORPHIC ACETYLATION IN MAN

Carcinogenic

Arylamines

benzidine

-naphthylamine

4-aminobiphenyl

Hydrazines

isoniazid

hydralazine

phenylzine

acetylhydrazine

hydrazine

Arylamines

dapsone

procainamide

sulfamethazine

sulfapyridine

aminoglutethimide

Drugs metabolized to amines

sulfasalazine nitrazepam

clonazepam caffeine

slide19

ADVERSE EFFECTS TO SULFASALAZINE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Frequency of side effect

Slow AcetylatorsFast Acetylators

Side Effect

cyanosis

hemolysis

transient reticulocytosis

9 1

5 0

6 0

Data from: Das et al. N Engl J Med 289:491-495, 1973.

slide20

Relationship Between Onset of Lupus Syndrome in Fast and Slow Acetylators Receiving Procainamide.Data from: Woosley RL, et al. N Engl J Med 298:1157-1159, 1978.

slide21

Distribution of acetylator phenotype in control subjects and those experiencing a sulfonamide hypersensitivity reaction.

Rieder et al. Clin Pharmacol Ther 49:13-17, 1991.

slide22

UDPGT

NAT1

SMX-glucuronide

N-acetyl-SMX

CYP2C9

MPO

PGH SYNTHASE

NAT1

Hydroxamic

acid

Detox

Nitroso

SMX hydroxylamine

O-acetylation

N,O-AT

Covalent binding to

cellular macromolecules/

cytotoxicity

Acetoxy ester

Detoxified metabolite

Hypersensitivity/

Adverse Reaction

slide23

Future Role of SNPs and Pharmacogenetics

SNP - Single Nucleotide Polymorphisms

……. G G T A A C T G ……

……. G G C A A C T G …...

AS of February 2001, 1.42 million SNPs had been identified in the human genome.

slide24

Patients with efficacy

in clinical trials

Patients without efficacy

in clinical trials

Predictive of efficacy

Predictive of no efficacy