Pharmacogenetics: Improvement of Existing Drug Treatments

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Pharmacogenetics Improvement of Existing Drug
Treatments

• Zhou Yan-Qiong

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Background

• 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
gt1
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Normal Distribution
Frequency
Activity
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Polymorphic Distribution
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GENETIC POLYMORPHISMS
Pharmacokinetic
Pharmacodynamic

• Receptors
• Ion channels
• Enzymes
• Immune molecules

• Transporters
• Plasma protein binding
• Metabolism

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II. Genetic polymorphisms in drug metabolizing
enzymes
From Evans WE, Relling MV. Pharmacogenomics
Translating functional genomics into rational
therapeutics. Science 286487-491, 1999.
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Genetic polymorphisms in drug metabolizing enzymes

• 1. Polymorph of debrisoquine
• extensive metabolizerEM
• poor metabolizer PMgt12.6
• recessive transmission,autosomal

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DRUGS WHOSE METABOLISM CO-SEGREGATES WITH
DEBRISOQUINE
alprenolol amitriptyline bufuralol clomipramine c
odeine desipramine encainide ethylmorphine flecai
nide fluoxetine guanoxan imipramine metoprolol no
rtriptyline paroxetine phenformin propafenone p
ropranolol
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2. Polymorph of Mephenetoin

• EM
• PMrecessive transmission,autosomal
• racial diversify

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3. Glucose-6-phosphate dehydrogenase activity
Effects gt300 million worldwide
CYP MPO PGH Synthase
R-NH2
R-NOH
ERYTHROCYTE
O2
NADP or GSSG(?)
NAD
HgbFe2
R-NOH
HMP Shunt G-6-PD Dependent
MetHgb Reductase
NADPH or GSH(?)
R-NO
HgbFe3
NADH
Reactive Oxygen
GSH
Splenic Sequestration
Semi-mercaptal
SOD Catalase GSH Peroxidase
sulfinamide
Detoxification
Hemolytic Anemia
R-NH2
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Drugs and Chemicals Unequivocally Demonstrated to
Precipitate Hemolytic Anemia in Subjects with
G6PD Deficiency
Acetanilide Nitrofurantoin Primaquine Methylene
Blue Sulfacetamide Nalidixic Acid Naphthalene Sulf
anilamide Sulfapyridine Sulfamethoxazole
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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 lt4 Iranians 8 Gre
eks 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 lt1
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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 2485, 1960.
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ETHNIC DIFFERENCES IN THE DISTRIBUTION OF
ACETYLATOR PHENOTYPE
Population Slow Hetero Fast Homo Fast
South Indians 59 35.6 5.4 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 7373-4000, 1982.
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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 nitrazep
am 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 cyanosis
hemolysis transient reticulocytosis
9 1 5 0 6 0
Data from Das et al. N Engl J Med 289491-495,
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
2981157-1159, 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 4913-17, 1991.
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NAT1
UDPGT
N-acetyl-SMX
SMX-glucuronide
CYP2C9 MPO PGH SYNTHASE
NAT1
Nitroso
Detox
Hydroxamic acid
SMX hydroxylamine
O-acetylation
N,O-AT
Covalent binding to cellular macromolecules/ cytot
oxicity
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