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Pharmacogenetics: Improvement of Existing Drug Treatments

Zhou Yan-Qiong

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BackgroundBackground ：

• Clinical genetics• Cytogenetic• Somatic Cell Genetics• Biochmical genetics• Molecular genetics• Cancer genetics• Population genetics• Immunogenetics• Pharmacogenetics• Genetic toxicology• Developmental genetics• Behavior genetics

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PHARMACOGENETICS

The study of genetically controlled variations in drug response

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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%

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Normal Distribution

Fre

qu

ency

Fre

qu

ency

ActivityActivity

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Polymorphic Distribution

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GENETIC POLYMORPHISMS

Pharmacokinetic Pharmacodynamic

•Transporters•Plasma protein binding•Metabolism

•Receptors•Ion channels•Enzymes•Immune molecules

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

II. Genetic polymorphisms in drug metabolizing enzymes

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Genetic polymorphisms in drug metabolizing enzymes

• 1. Polymorph of debrisoquine• extensive metabolizer——EM• poor metabolizer ——PM*＞ 12.6• recessive transmission,autosomal

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DRUGS WHOSE METABOLISM CO-SEGREGATES WITH DEBRISOQUINE

alprenolol amitriptyline bufuralol clomipraminecodeine desipramine encainide ethylmorphineflecainide fluoxetine guanoxan imipraminemetoprolol nortriptyline paroxetine phenforminpropafenone propranolol

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• EM• PM： recessive transmission,autosomal

• racial diversify

2. Polymorph of Mephenetoin：

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3. Glucose-6-phosphate dehydrogenase activityEffects >300 million worldwide

R-NH2 CYP MPOPGH Synthase

R-NOH

ERYTHROCYTE

R-NOH

O2

HgbFe+2

R-NO HgbFe+3

Reactive Oxygen

NADH

NAD+MetHgbReductase

NADPHor GSH(?)

NADP+ or GSSG(?)HMP Shunt

G-6-PDDependent

SODCatalaseGSH Peroxidase

Detoxification

SplenicSequestration

Hemolytic Anemia

GSH

Semi-mercaptal

sulfinamide

R-NH2

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Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia

in Subjects with G6PD Deficiency

Acetanilide Nitrofurantoin PrimaquineMethylene Blue Sulfacetamide Nalidixic AcidNaphthaleneSulfanilamide SulfapyridineSulfamethoxazole

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INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS

Ethnic Group Incidence(%)Ashkenazic Jews 0.4Sephardic Jews Kurds 53 Iraq 24 Persia 15 Cochin 10 Yemen 5 North Africa <4

Iranians 8Greeks 0.7-3

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INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS

Ethnic Group Incidence(%)Asiatics Chinese 2 Filipinos 13 Indians-Parsees 16 Javanese 13 Micronesians <1

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4. N-ACETYLTRANSFERASE ACTIVITY

Distribution of plasma isoniazid concentration in 483 subjectsafter and oral dose. Reproduced from Evans DAP. Br Med J 2:485, 1960.

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ETHNIC DIFFERENCES IN THE DISTRIBUTION OF ACETYLATOR PHENOTYPE

Population % Slow % Hetero Fast % Homo Fast

South Indians 59 35.6 5.4Caucasians 58.6 35.9 5.5Blacks 54.6 38.6 6.8

Eskimos 10.5 43.8 45.7Japanese 12 45.3 42.7Chinese 22 49.8 28.2

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

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XENOBIOTICS SUBJECT TO POLYMORPHIC ACETYLATION IN MAN

Hydrazines isoniazid hydralazine phenylzineacetylhydrazine hydrazine

Arylamines dapsone procainamide sulfamethazine sulfapyridineaminoglutethimide

Carcinogenic Arylamines benzidine-naphthylamine4-aminobiphenyl

Drugs metabolized to aminessulfasalazine nitrazepamclonazepam caffeine

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ADVERSE EFFECTS TO SULFASALAZINE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

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

Side Effect cyanosis hemolysistransient reticulocytosis

Frequency of side effectSlow Acetylators Fast Acetylators

9 15 06 0

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0

20

40

60

80

100

120

0 20 40 60 80 100

Duration of Therapy (months)

% o

f p

ts w

ith

lup

us

Slow Acetylators

Fast Acetylators

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.

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

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

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NAT1N-acetyl-SMX

UDPGTSMX-glucuronide

CYP2C9MPOPGH SYNTHASE

SMX hydroxylamineNitrosoDetox

Covalent binding tocellular macromolecules/

cytotoxicity

Hypersensitivity/Adverse Reaction

O-acetylation

Acetoxy ester

NAT1Hydroxamicacid

N,O-AT

Detoxified metabolite

Sulfamethoxazole(SMX)

NO

NH2 S

O

O

HN

CH3

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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.

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Patients with efficacyin clinical trials

Patients without efficacyin clinical trials

Predictive of efficacy

Predictive of no efficacy