PHAR 751 Pharmacogenomics

Sarah Brown, Pharm.D.Pharmacy Practice Resident

Asante Health Systemsbrown@asante.org

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

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.

Drescher, et al. MDR1 gene polymorphisms and disposition of the p-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002;53:526-534.

Fexofenadine concentration vs. Time

CC vs. TT genotype

■ CC○ TT

GG vs. TT phenotype

Fexofenadine concentration vs. Time

■ GG○ TT

Not significant

Drescher, et al. MDR1 gene polymorphisms and disposition of the p-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002;53:526-534.

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

• 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

NAT2 polymorphism: Isoniazid

Slow acetylator vs. Fast acetylator

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

(a) =Requires metabolism before N-acetylation

CYP2C polymorphismsEnzyme Drug Interaction

CYP2C9 Warfarin

Glipizide

Tolbutamide

Phenytoin

↑ bleeding, ↑ incidence of severe bleeding in PMs

Possiblility of low BS in PMs

Signs of overdose; ataxia, disturbances of consciousness, mental confusion

CYP2C19 Diazepam

Omeprazole

Prolonged sedation in PMs, unconsciuosness (Asian population)

Reports of ↓ cure rates at low dosages in EMs

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

Genetic testing

• Carrier testing

• Diagnostic testing

• Newborn screening

• Pharmacogenetic testing

Clinical Relevance

• Small numbers of patients

• Availability of genotyping and phenotyping tools– Genetic testing– Predicting

• Drug interactions

• Therapeutic window

• In practice…