Lecture 18: Pharmacogenomics Flashcards
Paradox of Drug Development and Use
- Clinical trials provide evidence of efficacy and safety at usual doses in populations
2. Physicians treat individual patients who can vary widely in their response to drug therapy
Pharmacogenetics:
is the Study of Inherited Differences (Variation) in Drugs Metabolism & Response
•Genetic Variability Can Affect:
systemic genomic analysis in populations of treated subjects to identify variants that predict drug response including the occurrence of adverse reactions.
Study the influence of genetic variations on drug responses in patients by correlating gene expression of single-nucleotide polymorphism (SNP) to drug’s efficacy and toxicity.
Pharmacokinetics:
Plasma Clearance, Delivery of Drug or Metabolite to Target Cells
Pharmacodynamics
The Relationship Between the Drug Concentration & Its Therapeutic Effect.
–The Likelihood of an Adverse Reaction
Mutations in the Genome that Affect Gene Expression
-One in every 1200 bases may be different in any
two humans. This variation, which is called a polymorphism, is largely responsible for differences between how humans respond to drugs.
Polymorphism in the enhances, promoters or intron/exon boundary all can affect the expression of genes.
Leukemia
Converted to nucleotides for incorporation into DNA by hypoxyxanthine phosphoribosyl transferase (HPRT).
Mercaptopurine-derived products block DNA replication and lead to tumor cell death.
Mercaptopurine metabolism
Thiopurine methyltransferase (TPMT) converts mercaptopurine into an inactive metabolite called methylmercaptopurine.
- 90% homozygous for wild type allele and metabolize product normally; Toxicity is low, but relapse is high. - Some are poor metabolizers; Toxicity is high. - 0.3% are homozygous for these variants; High risk of myelosuppression and secondary tumors.
Clinical Consequences of TPMT
Polymorphism
High TPMT: decrease therapeutic effect
Low TPMP: increase toxicity
