PHAR 751 Pharmacogenomics

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PHAR 751 Pharmacogenomics

• Sarah Brown, Pharm.D.
• Pharmacy Practice Resident
• Asante Health System
• sbrown_at_asante.org

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PK p-gp sex, racial background
? Males Females ? African Americans ?European
Americans
? No difference between groups
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Genotype vs. Phenotype exon 26
MDR1 exon 26, C3435T ? CT CC ? TT P0.036 CC
vs. TT
180 mg fexofenadine po
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Genotype vs. Phenotype exon 21
MDR1 exon 21, G2677T ? GT GG ? TT P 0.054 GG
vs. TT
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Genotype vs. Phenotype
MDR11 or MDR12 alleles ? 12 11 ? 22
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Study conclusions

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

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Another Fexofenadine, p-gp study

• Is the disposition of fexofenadine in humans
  affected by polymorphisms of MDR1?
• TT genotype vs. CC genotype

Drescher, et al. MDR1 gene polymorphisms and
disposition of the p-glycoprotein substrate
fexofenadine. Br J Clin Pharmacol 200253526-534.
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CC vs. TT genotype
CC ? TT
Fexofenadine concentration vs. Time
Drescher, et al. MDR1 gene polymorphisms and
disposition of the p-glycoprotein substrate
fexofenadine. Br J Clin Pharmacol 200253526-534.
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GG vs. TT phenotype
GG ? TT ? Not significant
Fexofenadine concentration vs. Time
Drescher, et al. MDR1 gene polymorphisms and
disposition of the p-glycoprotein substrate
fexofenadine. Br J Clin Pharmacol 200253526-534.
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Different conclusions?

• This study NS difference in PK of fexofenadine
• Known fexofenadine is a p-gp substrate
• Unknown lack of association btwn PK and
  polymorphism

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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

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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

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NAT2 polymorphism Isoniazid
Slow acetylator vs. Fast acetylator
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N-acetyltransferase (NAT2) polymorphism

• Europe, North America 40 70 slow acetylators
  (SA)
• Pacific Asian 10 30 SA
• Egyptian and Moroccan 80 90 SA
• Canadian Eskimo 5 SA

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Agents Undergoing Polymorphic N-acetylation

• Acebutolol (a)
• Isoniazid
• Aminobenzoic Acid
• Nitrazepama
• Aminogluthethimide
• Phenelzine
• Aminosalicylic Acid
• Procainamide
• Amrinone

• Sulfadiazine
• Caffeine (a)
• Sulfamerazine
• Clonazepam
• Sulfamethazine
• Dapsone
• Sulfapyridine
• Hydralazine
• Sulfasalazine

(a) Requires metabolism before N-acetylation
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CYP2C polymorphisms
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Consequences of enzyme polymorphisms

• ? CYP1A activity slow acetylation ?
  myelosuppression from active metabolites of
  amonafide
• ? drug-metabolizing enzyme ? ? pro-drug
  activation
• CYP2D6, opioid analgesics

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PK Ethnic differences

• Unlikely
• No gut or hepatic first-pass effect
• Low plasma protein-binding (lt70-80)
• No/minimal hepatic metabolism
• No/minimal renal tubular secretion
• Likely
• Gut or hepatic metabolism
• High plasma protein-binding
• Hepatic metabolism as major route

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Ethnic differences hepatic metabolism

• Chinese vs. Caucasians
• Higher metabolism
• Propranolol
• Morphine
• No difference
• Triazolam
• Cerivastatin

• Lower metabolism
• Desipramine
• Alprazolam
• Diazepam
• Omeprazole
• Nifedipine
• Codeine

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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

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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

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Genetic testing

• Carrier testing
• Diagnostic testing
• Newborn screening
• Pharmacogenetic testing

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Clinical Relevance

• Small numbers of patients
• Availability of genotyping and phenotyping tools
• Genetic testing
• Predicting
• Drug interactions
• Therapeutic window
• In practice