Phar 751 pharmacogenomics
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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.

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PHAR 751 Pharmacogenomics

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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


Cyp2c polymorphisms

CYP2C polymorphisms


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…


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