PHAR 751 Pharmacogenomics Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@asante.org

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

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 MDR1 exon 21, G2677T □ GT ■ GG ○ TT P= 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.

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 ○ 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? 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 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

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…