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PHAR 751 Pharmacogenomics Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System [email protected] Definitions • Pharmacology + Genomics = Pharmacogenomics • The study of how an individual’s genetic inheritance affects the body’s response to drugs 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 www.globecartoon.com/neweconomy/13.html Accessed 3/5/07 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 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. Pharmacogenomics • 20 – 95% of variability in drug disposition and effects • Sequence variants in genes encoding: – Drug-metabolizing enzymes – Drug transporters – Drug targets Genetic polymorphisms • Transporters • Drug transporters • Enzymes, Monooxygenases – Phase I • Oxidative reactions – Phase II • Acetylation • Glucuronidation • Methylation 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) 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 http://www.theonion.com/content/files/images/Infographic-Human-Genome-C.article.jpg 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 Polymorphism of: • Drug metabolism • Drug targets • Disease-modifying genes • Drug target polymorphism: β2-adrenoreceptor A: ↑ venodilation B: ↑ airway response C: ↑ desensitization Evans WE, McLeod HL. Pharmacogenomics – Drug Disposition, Drug Targets, and Side Effects. N Engl J Med 2003;348(6):538-549. 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 pgp variations in drug absorption 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. 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. 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. Statistically significant interethnic difference PK: p-gp & sex, racial background ∆ Males ■ Females ○ African Americans ▼European Americans No difference between groups Genotype vs. Phenotype: exon 26 MDR1 exon 26, C3435T □ CT ■ CC ○ TT P=0.036 CC vs. TT 180 mg fexofenadine po Genotype vs. Phenotype: exon 21 MDR1 exon 21, G2677T □ GT ■ GG ○ TT P= 0.054 GG vs. TT Genotype vs. Phenotype MDR1*1 or MDR1*2 alleles □ *1*2 ■ *1*1 ○ *2*2 Study conclusions • Multiple SNPs present in the human MDR1 gene • Polymorphism alters p-gp activity • Genetic variation differs d/t racial background 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 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 Consequences of enzyme polymorphisms • ↑ CYP1A activity + slow acetylation = ↓ myelosuppression from active metabolites of amonafide • ↓ drug-metabolizing enzyme ↓ pro-drug activation – CYP2D6, opioid analgesics 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 Ethnic differences: hepatic metabolism • Chinese vs. Caucasians – Higher metabolism • Propranolol • Morphine – No difference • Triazolam • Cerivastatin – Lower metabolism • • • • • • Desipramine Alprazolam Diazepam Omeprazole Nifedipine Codeine 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 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?