Chapter 4: pharmacogenetics

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Chapter 4 pharmacogenetics
RB Raffa, PhD
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Want to know for all drugs

• A Absorption
• D Distribution
• M Metabolism
• E Elimination
• MoA Mechanism of action
• AEs Adverse effects
• DIs Drug interactions
• Pt Patient characteristics

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Real life

• 6-mercaptopurine is used to treat acute
  lymphoblastic leukemia in children
• it is metabolized by TPMT (thiopurine
  methyltransferase)
• toxicity (overdose) leads to death
• what can we do?

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Pharmacogenetics Pharmacogenomics

• how genes (genotype) account for observed
  differences in response to drugs (phenotype)
• how information about genotype-phenotype can be
  used to predict or direct individualized
  medicine

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Background

• inherited information is carried in genes
  (specific strands of DNA on chromosomes)
• the total genetic information is the genome
• a gene encodes a specific sequence of amino acids
  (protein)
• transcription and translation occur when a gene
  is activated (by a promoter)
• the result of gene expression gene products

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Gene products
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Review Q

• Which is the non-coding region of a gene?
• (A) exon
• (B) intron
• (C) promoter
• (D) SNP

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Review Q

• The same gene can lead to different proteins
• (A) true
• (B) false

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Polymorphisms

• alternate forms of a gene gt1 freq.
• polymorphism in any gene region can lead to
  altered activity of a gene product
• SNPs are the most common variants in humans

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SNP types

• synonymous non-synonymous

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Real life

• 6-mercaptopurine is used to treat acute
  lymphoblastic leukemia
• it is metabolized by TPMT (thiopurine
  methyltransferase)
• toxicity (overdose) in PMs of TPMT

standard dose
heterozygous
65 dose
6-10 dose
homozygous
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Review Q

• SNPs are defined as mutations that involve a
  single DNA base substitution that occurs with the
  frequency of at least ____ in a population.
• (A) 1
• (B) 10
• (C) gt50

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Review Q

• SNPs that do not lead to a change in a proteins
  amino acid sequence because of the redundancy in
  the genetic code are called ________ .
• (A) synonymous
• (B) non-synonymous

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Clinical example 1CYP2D6 codeine

• codeine as prodrug
• poor metabolizers underdose
• extensive or rapid metabolizers overdose

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Clinical example 2warfarin

• http//www.healthanddna.com/WarfarinGenetics/Warfa
  rinGenetics_viewlet_swf.html

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• end