1. PHAR 751 Pharmacogenomics
Sarah Brown, Pharm.D.
Pharmacy Practice Resident
Asante Health System

2. PK: p-gp & sex, racial background
∆ Males
■ Females
○ African Americans
▼European Americans
 No difference between groups

3. Genotype vs. Phenotype: exon 26
MDR1 exon 26, C3435T
□ CT
■ CC
○ TT
P=0.036 CC vs. TT
180 mg fexofenadine po

4. Genotype vs. Phenotype: exon 21
MDR1 exon 21, G2677T
□ GT
■ GG
○ TT
P= GG vs. TT

5. Genotype vs. Phenotype
MDR1*1 or MDR1*2 alleles
□ *1*2
■ *1*1
○ *2*2

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

7. 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:

8. 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:

9. 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:

10. 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

11. 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

12. 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

13. NAT2 polymorphism: Isoniazid
Slow acetylator vs. Fast acetylator

14. 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

15. 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

16. CYP2C polymorphisms Enzyme Drug Interaction CYP2C9 CYP2C19 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

17. Consequences of enzyme polymorphisms
↑ CYP1A activity + slow acetylation = ↓ myelosuppression from active metabolites of amonafide
↓ drug-metabolizing enzyme  ↓ pro-drug activation
CYP2D6, opioid analgesics

18. 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

19. Ethnic differences: hepatic metabolism
Chinese vs. Caucasians
Higher metabolism
Propranolol
Morphine
No difference
Triazolam
Cerivastatin
Lower metabolism
Desipramine
Alprazolam
Diazepam
Omeprazole
Nifedipine
Codeine

20. 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

21. 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

22. Genetic testing Carrier testing Diagnostic testing Newborn screening
Pharmacogenetic testing

23. Clinical Relevance Small numbers of patients
Availability of genotyping and phenotyping tools
Genetic testing
Predicting
Drug interactions
Therapeutic window
In practice…