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PHAR 751 Pharmacogenomics

PHAR 751 Pharmacogenomics. Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@asante.org. Definitions. Pharmacology + Genomics = Pharmacogenomics The study of how an individual’s genetic inheritance affects the body’s response to drugs. More definitions.

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PHAR 751 Pharmacogenomics

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  1. PHAR 751 Pharmacogenomics Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@asante.org

  2. Definitions • Pharmacology + Genomics = Pharmacogenomics • The study of how an individual’s genetic inheritance affects the body’s response to drugs

  3. 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

  4. www.globecartoon.com/neweconomy/13.html Accessed 3/5/07

  5. 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

  6. 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.

  7. Pharmacogenomics • 20 – 95% of variability in drug disposition and effects • Sequence variants in genes encoding: • Drug-metabolizing enzymes • Drug transporters • Drug targets

  8. Genetic polymorphisms • Transporters • Drug transporters • Enzymes, Monooxygenases • Phase I • Oxidative reactions • Phase II • Acetylation • Glucuronidation • Methylation

  9. 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)

  10. 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

  11. http://www.theonion.com/content/files/images/Infographic-Human-Genome-C.article.jpghttp://www.theonion.com/content/files/images/Infographic-Human-Genome-C.article.jpg

  12. 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

  13. Polymorphism of: • Drug metabolism • Drug targets • Disease-modifying genes

  14. Drug target polymorphism: β2-adrenoreceptor A: ↑ venodilation B: ↑ airway response C: ↑ desensitization

  15. Evans WE, McLeod HL. Pharmacogenomics – Drug Disposition, Drug Targets, and Side Effects. N Engl J Med 2003;348(6):538-549.

  16. 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

  17. 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; 358:383-4.

  18. 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 2001;70(2):189-199.

  19. 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 2001;70(2):189-199.

  20. Statistically significant interethnic difference

  21. PK: p-gp & sex, racial background ∆ Males ■ Females ○ African Americans ▼European Americans  No difference between groups

  22. Genotype vs. Phenotype: exon 26 MDR1 exon 26, C3435T □ CT ■ CC ○ TT P=0.036 CC vs. TT 180 mg fexofenadine po

  23. Genotype vs. Phenotype: exon 21 MDR1 exon 21, G2677T □ GT ■ GG ○ TT P= 0.054 GG vs. TT

  24. Genotype vs. Phenotype MDR1*1 or MDR1*2 alleles □ *1*2 ■ *1*1 ○ *2*2

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

  26. 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

  27. 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

  28. Consequences of enzyme polymorphisms • ↑ CYP1A activity + slow acetylation = ↓ myelosuppression from active metabolites of amonafide • ↓ drug-metabolizing enzyme  ↓ pro-drug activation • CYP2D6, opioid analgesics

  29. PK: Ethnic differences • Unlikely: • No gut or hepatic first-pass effect • Low plasma protein-binding (<70-80%) • No/minimal hepatic metabolism • No/minimal renal tubular secretion • Likely: • Gut or hepatic metabolism • High plasma protein-binding • Hepatic metabolism as major route

  30. Chinese vs. Caucasians Higher metabolism Propranolol Morphine No difference Triazolam Cerivastatin Lower metabolism Desipramine Alprazolam Diazepam Omeprazole Nifedipine Codeine Ethnic differences: hepatic metabolism

  31. African descent vs. Caucasians Higher metabolism Propranolol Lower metabolism Nifedipine Methyprednisolone Phenytoin No difference Metoprolol/labetolol Albuterol Terbutaline Trimazosin Procainamide Etoposide Ethnic differences: hepatic metabolism

  32. 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?

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