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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. - PowerPoint PPT Presentation
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PHAR 751 Pharmacogenomics
Sarah Brown, Pharm.D.Pharmacy Practice Resident
Asante Health [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 p-
gp
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
180 mg fexofenadine po
MDR1 exon 26, C3435T□ CT■ CC○ TTP=0.036 CC vs. TT
Genotype vs. Phenotype: exon 21
MDR1 exon 21, G2677T□ GT■ GG○ TTP= 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?