phar 751 pharmacogenomics
Download
Skip this Video
Download Presentation
PHAR 751 Pharmacogenomics

Loading in 2 Seconds...

play fullscreen
1 / 23

PHAR 751 Pharmacogenomics - PowerPoint PPT Presentation


  • 105 Views
  • Uploaded on

PHAR 751 Pharmacogenomics. Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System [email protected] PK: p-gp & sex, racial background. ∆ Males ■ Females ○ African Americans ▼European Americans.  No difference between groups. Genotype vs. Phenotype: exon 26.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'PHAR 751 Pharmacogenomics' - edolie


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
phar 751 pharmacogenomics

PHAR 751 Pharmacogenomics

Sarah Brown, Pharm.D.

Pharmacy Practice Resident

Asante Health System

[email protected]

pk p gp sex racial background
PK: p-gp & sex, racial background

∆ Males

■ Females

○ African Americans

▼European Americans

 No difference between groups

genotype vs phenotype exon 26
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
Genotype vs. Phenotype: exon 21

MDR1 exon 21, G2677T

□ GT

■ GG

○ TT

P= 0.054 GG vs. TT

genotype vs phenotype
Genotype vs. Phenotype

MDR1*1 or MDR1*2 alleles

□ *1*2

■ *1*1

○ *2*2

study conclusions
Study conclusions
  • Multiple SNPs present in the human MDR1 gene
  • Polymorphism alters p-gp activity
  • Genetic variation differs d/t racial background
another fexofenadine p gp study
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 2002;53:526-534.

cc vs tt genotype
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 2002;53:526-534.

gg vs tt phenotype
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 2002;53:526-534.

different conclusions
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
polymorphisms enzymes
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
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
nat2 polymorphism isoniazid
NAT2 polymorphism: Isoniazid

Slow acetylator vs. Fast acetylator

n acetyltransferase nat2 polymorphism
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
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

Agents Undergoing Polymorphic N-acetylation

(a) =Requires metabolism before N-acetylation

consequences of enzyme polymorphisms
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
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
ethnic differences hepatic metabolism1
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
ethnic variations
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
genetic testing
Genetic testing
  • Carrier testing
  • Diagnostic testing
  • Newborn screening
  • Pharmacogenetic testing
clinical relevance
Clinical Relevance
  • Small numbers of patients
  • Availability of genotyping and phenotyping tools
    • Genetic testing
    • Predicting
  • Drug interactions
  • Therapeutic window
  • In practice…
ad