Download Review of Intestinal Drug Absorption and Intestinal

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)
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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
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Desipramine
Alprazolam
Diazepam
Omeprazole
Nifedipine
Codeine
Ethnic differences: hepatic
metabolism
• African descent vs. Caucasians
– Higher metabolism
• Propranolol
– Lower metabolism
• Nifedipine
• Methyprednisolone
• Phenytoin
– No difference
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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?