PHAR 751 Pharmacogenomics

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PHAR 751 Pharmacogenomics

• Sarah Brown, Pharm.D.
• Pharmacy Practice Resident
• Asante Health System
• sbrown_at_asante.org

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Definitions

• Pharmacology Genomics Pharmacogenomics
• The study of how an individuals genetic
  inheritance affects the bodys response to drugs

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More definitions

• Genotype
• Genetic constitution of an individual
• Gene combination at one specific locus or any
  specified combination of loci
• Phenotype
• Observable trait
• Manifestation of a genotype

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www.globecartoon.com/neweconomy/13.html Accessed
3/5/07
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Human Genome Project

• Sequenced the human genome 3 billion base pairs
• 30,000 genes in human DNA
• Human DNA (4 nucleotides)
• 3 nucleotides 1 codon
• 1 codon 1 amino acid (aa)
• Many codons 1 gene
• Thousands of genes 1 chromosome

http//www.genique.com/images/codage_genes.gif
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Polymorphisms

• A mutation in genetic code that occurs in 1 of
  the population
• Discontinuous genetic variation resulting in the
  occurrence of several different forms or types of
  individuals w/in a single species.

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Pharmacogenomics

• 20 95 of variability in drug disposition and
  effects
• Sequence variants in genes encoding
• Drug-metabolizing enzymes
• Drug transporters
• Drug targets

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Genetic polymorphisms

• Transporters
• Drug transporters
• Enzymes, Monooxygenases
• Phase I
• Oxidative reactions
• Phase II
• Acetylation
• Glucuronidation
• Methylation

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Types of polymorphisms

• Single Nucleotide Polymorphism (SNP) single base
  difference in DNA sequence
• Insertion/deletion polymorphism
• Synonymous SNP does not result in change in aa
  (CCA and CCG proline)
• Non-synonymous SNP results in change in aa (AGC
  and GGC serine, glycine)

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SNPs

• Responsible for 90 of all genetic variation
• ? Predispose person to a disease
• ? Influence response to a drug

Human Genome Project Information website.
http//www.ornl.gov/sci/techresources/Human_Genome
/faq/snps.shtml Accessed 3/4/07
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http//www.theonion.com/content/files/images/Infog
raphic-Human-Genome-C.article.jpg
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Polymorphism examples

• Higher organisms male and female sexes
• Humans different blood types
• A polymorphism that persists over many
  generations is usually maintained b/c no single
  form has an overall advantage or disadvantage
• ? Some polymorphisms have no visible
  manifestation

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Polymorphism of

• Drug metabolism
• Drug targets
• Disease-modifying genes

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• Drug target polymorphism ß2-adrenoreceptor
• A ? venodilation
• B ? airway response
• C ? desensitization

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Evans WE, McLeod HL. Pharmacogenomics Drug
Disposition, Drug Targets, and Side Effects. N
Engl J Med 2003348(6)538-549.
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P-gp polymorphism

• MDR1 is polymorphic
• 25 mutations identified
• The C3435T polymorphism p-gp expression in the
  intestine
• Homozygous for the T allele ? ? lower intestinal
  p-gp
• ? variations in drug absorption

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Differences in allele frequency Ethnicity

• C3435T polymorphism
• Homozygous for C allele
• West Africans 83
• African Americans 61
• Whites 26
• Japanese 34
• More or less p-gp?

Schaeffeler, et al. Frequency of C3435T
polymorphism of MDR1 gene in African people. The
Lancet. 2001 358383-4.
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Study MDR1 alleles

• To identify SNPs in coding region of MDR1 gene
• To assess prevalence in European American and
  African American populations
• To investigate the possible functional
  significance of polymorphisms
• fexofenadine

Kim, et al. Identification of functionally
variant MDR1 alleles among European Americans and
African Americans. Clin Pharmacol Ther
200170(2)189-199.
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Study MDR1 alleles

• 60 patients
• 10 SNPs
• 6 nonsynonymous
• 4 synonymous
• MDR1

Kim, et al. Identification of functionally
variant MDR1 alleles among European Americans and
African Americans. Clin Pharmacol Ther
200170(2)189-199.
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?Statistically significant interethnic difference
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PK p-gp sex, racial background
? Males Females ? African Americans ?European
Americans
? No difference between groups
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Genotype vs. Phenotype exon 26
MDR1 exon 26, C3435T ? CT CC ? TT P0.036 CC
vs. TT
180 mg fexofenadine po
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Genotype vs. Phenotype exon 21
MDR1 exon 21, G2677T ? GT GG ? TT P 0.054 GG
vs. TT
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Genotype vs. Phenotype
MDR11 or MDR12 alleles ? 12 11 ? 22
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Study conclusions

• Multiple SNPs present in the human MDR1 gene
• Polymorphism alters p-gp activity
• Genetic variation differs d/t racial background

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Polymorphisms Enzymes

• Frequently polymorphic
• Phenotypic consequence
• Leads to inter-individual variability in drug
  response?
• Other factors molecular basis, expression of
  other drug-metabolizing enzymes, concurrent
  medications or illnesses

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Consequences of enzyme polymorphisms Drug
toxicities

• Thiopurine methyltransferase-deficiency
• Hematopoietic toxicity when treated w/ standard
  doses of azathioprine or mercaptopurine
• Slow acetylator phenotype
• Hydralazine-induced lupus
• Isoniazid-induced neuropathies
• Dye-associated bladder cancer
• Sulfonamide-induced hypersensitivity rxns

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Consequences of enzyme polymorphisms

• ? CYP1A activity slow acetylation ?
  myelosuppression from active metabolites of
  amonafide
• ? drug-metabolizing enzyme ? ? pro-drug
  activation
• CYP2D6, opioid analgesics

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PK Ethnic differences

• Unlikely
• No gut or hepatic first-pass effect
• Low plasma protein-binding (
• No/minimal hepatic metabolism
• No/minimal renal tubular secretion
• Likely
• Gut or hepatic metabolism
• High plasma protein-binding
• Hepatic metabolism as major route

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Ethnic differences hepatic metabolism

• Chinese vs. Caucasians
• Higher metabolism
• Propranolol
• Morphine
• No difference
• Triazolam
• Cerivastatin

• Lower metabolism
• Desipramine
• Alprazolam
• Diazepam
• Omeprazole
• Nifedipine
• Codeine

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Ethnic differences hepatic metabolism

• African descent vs. Caucasians
• Higher metabolism
• Propranolol
• Lower metabolism
• Nifedipine
• Methyprednisolone
• Phenytoin

• No difference
• Metoprolol/labetolol
• Albuterol
• Terbutaline
• Trimazosin
• Procainamide
• Etoposide

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Ethnic variations

• Passive absorption, filtration at the glomerulus,
  and passive tubular reabsorption will not differ
  between ethnic groups
• For many drugs, PK prediction is difficult
• Wide therapeutic window?
• Narrow therapeutic window?