Transcript pharm.med.stu.edu.cn

Pharmacogenetics: Improvement
of Existing Drug Treatments
Zhou Yan-Qiong
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Background ：
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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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Frequency
Normal Distribution
Activity
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Polymorphic Distribution
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GENETIC
POLYMORPHISMS
Pharmacokinetic
•Transporters
•Plasma protein binding
•Metabolism
Pharmacodynamic
•Receptors
•Ion channels
•Enzymes
•Immune molecules
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II. Genetic polymorphisms in drug metabolizing
enzymes
From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics
into rational therapeutics. Science 286:487-491, 1999.
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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 COSEGREGATES WITH DEBRISOQUINE
alprenolol amitriptyline
codeine
desipramine
flecainide fluoxetine
metoprolol nortriptyline
propafenone
bufuralol
encainide
guanoxan
paroxetine
propranolol
clomipramine
ethylmorphine
imipramine
phenformin
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2. Polymorph of Mephenetoin：
• EM
• PM：recessive transmission,autosomal
• racial diversify
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3. Glucose-6-phosphate dehydrogenase activity
Effects >300 million worldwide
RNH2
CYP
MPO
PGH Synthase
R-NOH
ERYTHROCYTE
HMP Shunt
G-6-PD
Dependent
NADP+ or
GSSG(?)
NADPH
or GSH(?)
O2
R-NOH
HgbFe+2
R-NO
HgbFe+3
GSH
Semi-mercaptal
sulfinamide
MetHgb
Reductase
Reactive
Oxygen
NADH
Splenic
Sequestration
SOD
Catalase
GSH Peroxidase
Detoxification
RNH2
NAD+
Hemolytic
Anemia
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Drugs and Chemicals Unequivocally
Demonstrated to Precipitate Hemolytic Anemia
in Subjects with G6PD Deficiency
Acetanilide
Nitrofurantoin
Methylene Blue
Sulfacetamide
Naphthalene
Sulfanilamide
Sulfamethoxazole
Primaquine
Nalidixic Acid
Sulfapyridine
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INCIDENCE OF G6PD DEFICIENCY IN
DIFFERENT ETHNIC POPULATIONS
Ethnic Group
Incidence(%)
Ashkenazic Jews
0.4
Sephardic Jews
Kurds
53
Iraq
24
Persia
15
Cochin
10
Yemen
5
North Africa
<4
Iranians
Greeks
8
0.7-3
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INCIDENCE OF G6PD DEFICIENCY IN
DIFFERENT ETHNIC POPULATIONS
Ethnic Group
Incidence(%)
Asiatics
Chinese
2
Filipinos
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Indians-Parsees
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Javanese
13
Micronesians
<1
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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.
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ETHNIC DIFFERENCES IN THE DISTRIBUTION OF
ACETYLATOR PHENOTYPE
Population
South Indians
Caucasians
Blacks
Eskimos
Japanese
Chinese
% Slow
% Hetero Fast
59
58.6
54.6
10.5
12
22
35.6
35.9
38.6
43.8
45.3
49.8
% Homo Fast
5.4
5.5
6.8
45.7
42.7
28.2
From: Kalo W. Clin Pharmacokinet 7:373-4000, 1982.
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XENOBIOTICS SUBJECT TO
POLYMORPHIC ACETYLATION IN MAN
Hydrazines
Arylamines
isoniazid
dapsone
hydralazine
procainamide
phenylzine
sulfamethazine
acetylhydrazine
sulfapyridine
hydrazine
aminoglutethimide
Carcinogenic
Arylamines
benzidine
-naphthylamine
4-aminobiphenyl
Drugs metabolized to amines
sulfasalazine
nitrazepam
clonazepam
caffeine
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ADVERSE EFFECTS TO
SULFASALAZINE IN PATIENTS WITH
INFLAMMATORY BOWEL DISEASE
Frequency of side effect
Slow Acetylators Fast Acetylators
Side Effect
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1
cyanosis
5
0
hemolysis
6
0
transient reticulocytosis
Data from: Das et al. N Engl J Med 289:491-495, 1973.
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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.
% of pts with lupus
120
100
80
60
Slow Acetylators
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Fast Acetylators
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0
0
20
40
60
80
100
Duration of Therapy (months)
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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.
Percentage of Subjects
100
Control
HS
80
60
40
20
0
SLOW
FAST
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O
SMX-glucuronide
UDPGT
NH2
S
O
H
N
NAT1
CH3
N
O
N-acetyl-SMX
Sulfamethoxazole
(SMX)
CYP2C9
MPO
PGH SYNTHASE
Detox
Nitroso
SMX hydroxylamine
NAT1
O-acetylation
Hydroxamic
acid
N,O-AT
Covalent binding to
cellular macromolecules/
cytotoxicity
Acetoxy ester
Detoxified metabolite
Hypersensitivity/
Adverse Reaction
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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 efficacy
in clinical trials
Patients without efficacy
in clinical trials
Predictive of efficacy
Predictive of no efficacy
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