Pharmacogenomics

Question 1

What are the four different phenotypes to categorize the effects that genetic polymorphisms have on individuals?

Answer 1

1) Poor metabolizers (PMs): lack a working enzyme
2) Intermediate metabolizers (IMs): are heterogeneous for one working, wild-type allele and one mutant allele (or two reduced-function alleles)
3) Extensive metabolizers (EMs): have two normally functioning alleles
4) Ultrarapid metabolizers (UMs): have more than one functioning copy of a certain enzyme

Question 2

What happens during drug metabolism?

Answer 2

• Drug metabolism generally involves the conversion of lipophilic substances and metabolites into more easily excretable water-soluble forms
• Usually takes place in the liver

Question 3

What are the two major categories of drug metabolism?

Answer 3

• Phase I: oxidation, reduction, and hydrolysis reactions

- Phase II: conjugation reactions

Question 4

What are the Clinical Implications of Genetic Polymorphisms on poor to intermediate metabolizers?

Answer 4

Poor to intermediate metabolizers:

• Have a slow effect on drug metabolism
• Prodrug will be metabolized slowly into active drug metabolite. May have accumulation of prodrug.
• Active drug will be metabolized slowly into inactive metabolite. Potential for accumulation of active drug. Patient requires lower dosage of medication.

Question 5

What are the Clinical Implications of Genetic Polymorphisms on ultrarapid metabolizers?

Answer 5

Ultrarapid metabolizers:

• Have a fast effect on drug metabolism
• Prodrug rapidly metabolized into active drug. No dosage adjustment needed.
• Active drug rapidly metabolized into inactive metabolites leading to potential therapeutic failure. Patient requires higher dosage of active drug.

Question 6

Where are CYPs are generally located?

Answer 6

• In the endoplasmic reticulum (ER) and the mitochondria in human cells, of which the ER isoforms are of particular importance to the field of drug metabolism.
• In terms of their organ distribution, they are found in greater amounts in the liver and the intestine.

Question 7

Give examples of common drugs the CYP2D6 gene acts on.

Answer 7

CYP2D6 
Substrate               Inhibitors             Inducers 
Codeine             Amiodarone         Carbamazepine Dextromethorphan   Fluoxetine   Phenytoin Metoprolol              Labetalol        Phenobarbital Paroxetine             Paroxetine          Rifampin Haloperidol          Propafenone 
Propranolol          Quinidine 
Risperidone           Sertraline 
Timolol                   Cimetidine 
Amitriptyline 
Nortriptyline 
Clozapine 
Morphine 
Methadone

Question 8

Give examples of the common drugs the CYP3A4 enzyme acts on.

Answer 8

CYP3A4
Substrate Inhibitors Inducers Cyclosporine,FK506ErythromycinCarbamazepine Corticosteroids Clarithromycin Phenobarbital Erythromycin Diltiazem Rifampin Felodipine, isradipine Ketoconazole Rifabutin Nifedipine Fluconazole Phenytoin Nisoldipine Itraconazole Corticosteroids Nitrendipine Quinidine INH
Digoxin, quinidine Grapefruit juice St. John’s wort Verapamil Cimetidine
Warfarin Indinavir
Sildenafil Fluoxetine
Astemizole Zileuton, zafirlukast Terfenadine Verapamil
Pioglitazone Amiodarone
R-warfarin Corticosteroids.
Fluvoxamine

Question 9

Which 4 drugs are required to have pharmacogenetic testing prior to prescribing?

Answer 9

cetuximab, trastuzumab, maraviroc, and dasatinib.

• Cetuximab treatment needs a confirmation of epidermal growth factor receptor (EGFR) expression.
• Trastuzumab therapy requires testing for HER2/NEU overexpression.
• Infection with CCR-5-tropic HIV-1 should be confirmed before initiation of therapy with maraviroc (an antiretroviral).
• Dasatinib is used for the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of prior therapy