Pharmacogenomics Flashcards
What is pharmacogenomics?
- The influence of genetic variation on drug response
- Correlating gene expression or polymorphism with a drug’s efficacy or toxicity.
What are the goals of pharmacogenomics?
- Maximizing efficacy
- Minimizing toxicity
- Predicting patient response for personalized medicine
- Aiding in drug development.
What is the difference between pharmacogenetics and pharmacogenomics?
Pharmacogenetics
* individual gene-drug interactions,
* Involving one or two genes with a dominant effect on drug response.
Pharmacogenomics
* study of genomic influence on drug response
* often using high-throughput data to study complex interactions.
What is the potential of pharmacogenomics?
To guide the choice of drug and dose on an individual basis based on genetic information
leading to personalized medicine.
What is a mutation?
- A difference in the DNA code that occurs in less than 1% of the population
- Associated with rare diseases.
- Cystic fibrosis, sickle cell anemia, Huntingtons disease
What is a polymorphism?
- A difference in the DNA code that occurs in more than 1% of the population.
- Less likely to be the main cause of disease
- No visible clinical impact
What is a single nucleotide polymorphism (SNP)?
DNA sequence variation that occurs when a single nucleotide in the genome sequence is altered.
* Occur in at least 1% of the population
* Make up about 90% of all human genetic variation.
* They can be inherited or can arise as cells divide.
How can SNPs affect drug response?
Causes changes in
* drug metabolism (pharmacokinetics)
* drug targets (pharmacodynamics)
such as enzymes, receptors, or transporters
What are cytochrome P450 enzymes, and why are they important in pharmacogenomics?
- Group of enzymes that are commonly found with SNPs
- Primary driver in breaking down around 50% of prescription drugs in our body.
- Variations in expression and regulation of CYPs can lead to differences in drug response, making them targets for pharmacogenomics research.
What is the role of CYP enzymes in drug metabolism?
Responsible for metabolizing most clinically important drugs.
What is CYP2D6?
CYP2D6 is an enzyme that metabolizes about 25% of all drugs in the body
What is the role of CYP2D6 in the conversion of codeine to morphine?
CYP2D6 is responsible for the O-demethylation reaction that drives the conversion of codeine to morphine.
How does a polymorphism in the CYP2D6 gene affect codeine metabolism?
Can cause low metabolism of drugs which results in a lack of conversion of codeine into morphine.
What happens if there is an inactive polymorphism in CYP2D6?
The conversion of codeine to morphine will not occur, resulting in the prodrug being ineffective.
What is the prevalence of inactive polymorphisms?
5-10% in European Caucasians
Less than 2% in Southern Asians.
What is the role of CYP2D6 in the metabolism of tamoxifen?
Responsible for the metabolism of tamoxifen into its active metabolites
which are more effective at preventing the recurrence of breast cancer.
What is acetylation and what is an example of a drug that undergoes this process?
- A phase II reaction in which an acetyl group is added to a drug or metabolite.
- Isoniazid - treats tuberculosis
What is the role of N-acetyltransferase in the acetylation of isoniazid?
The enzyme responsible for acetylating isoniazid.
What is the difference between fast and slow acetylators in drug metabolism?
Differ in their ability to metabolize drugs through the enzyme N-acetlytransferase.
What is the difference in blood levels of isoniazid between fast and slow acetylators?
Blood levels are 4-6 times higher in slow acetylators than in fast acetylators.
What happens when isoniazid undergoes fast or slow acetylation?
Results in diversion to two separate toxic pathways.
How does acetylation of isoniazid differ between different ethnic populations?
Slow acetylators
45% of Caucasian and African-American populations in the US
Some Europeans
Fast acetylators
>90% of Asian and Inuit populations in US
What is the Roche AmpliChip P450 Test used for?
An aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics.
How does Roche AmpliChip P450 Test work?
by identifying a patient’s CYP2D6 and CYP2C19 genotype from genomic DNA extract.
