-
Define Mutation:
alterations in the DNA (genetic) code occurring <1% of the time in the population
-
Define Polymorphisms:
alterations in the DNA (genetic) code occurring >1% of the time in the population
-
Define Single-nucleotide polymorphisms (SNP):
single base pair difference in DNA; occur on very chromosome
-
What is a codon?
3 nucleotides
-
What enzymes mediate Phase I Metabolism and what is their usual mechanism?
- Cytochrome P-450 (CYP)
- Oxidation
-
What enzymes mediate Phase II Metabolizing Enzymes and what is their usual mechanism?
- N-acetyltransferase
- Glutathione S-transferase
- Glucuronidation
-
Which enzyme is going to be the most common isoenzyme associated with polymorphisms?
CYP2D6
-
What are populations of poor CYP2D6 metabolizers?
6.8% Sweden; 1% China
-
What drugs are metabolized by CYP2D6?
-
What are populations of poor CYP2C9 metabolizers?
3% England
-
What drugs are metabolized by CYP2C9?
-
What are populations of poor CYP2C19 metabolizers?
-
What drugs are metabolized by CYP2C19?
- Omeprazole
- Clopidegrel (Plavix)
-
What are populations of poor Dihydropyrimidine dehydrogenase metabolizers?
1% heterozygous of entire population
-
What drugs are metabolized by Dihydropyrimidine dehydrogenase?
5-Fluorouracil
-
What are populations of poor Uridine diphosphate-glucuronosyltransferase 1A1 metabolizers?
10% among whites
-
What drugs are metabolized by Uridine diphosphate-glucuronosyltransferase 1A1?
Irinotecan
-
What are populations of poor Thiopurine S-methyltransferase metabolizers?
- ~ 1/300 whites
- ~1/2500 Asians
-
What drugs are metabolized by Thiopurine S-methyltransferase?
Mercaptopurine
-
Which enzyme has the most well characterized polymorphisms?
CYP2D6
-
What percent of drugs does CYP2D6 meatabolize?
25-50%
-
What are general drug types are CYP2D6 substrates?
- Antidepressants
- Antiarrhythmics
- B-adrenergic antagonists
- Prodrugs such as codeine, tramadol and tamoxifen
-
What percent of Caucasians and African Americans are poor CYP2D6 metabolizers?
- 7-10% of Caucasians
- 15-20% of African Americans
-
What drugs are CI with Tamoxifen b/c they are strong CYP2D6 inhibitors?
SSRIs = Prozac, Paxil and Zoloft
-
What drugs were given as examples of CYP2D6 inhibitors?
- Amiodarone
- Chloroquine
- Cimetidine
- Clomipramine
- Diphenhydramine
- Duloxetine
- Fluoxetine
- Hydroxychloroquine
- Paroxetine
- Propafenone
- Propoxyphene
- Quinidine
- Terbinafine
-
What group of patients may have poor CYP2C19 metabolism?
Japanese and Chinese = 20%
-
What group of patients has a very low rate of CYP2C19 metabolism?
Caucasians (3-5%)
-
What are the main drugs involved in CYP2C19 metabolism?
- Omeprazole - PPIs
- Voriconazole
- Phenytoin
- Clopidogrel
-
CYP2C19 has what effect on PPIs, like Omeprazole?
Inactivates = PM have better cure rates than UM
-
How many different variants of CYP2C19 are there?
25
-
Why is it hard to tell what type of CYP2C19 metabolizer a person is?
25 different variants
-
What enzyme mainly metabolizes Clopidigrel?
CYP2C19
-
What are all the enzymes involved in Clopidegrel metabolism?
2C9, 2B6 and 2C19
-
What are the implications of PM CYP2C19 metabolism of clopidegrel?
- 20-40% of patients do not receive benefit from clopidegrel
- Clopidegrel is a prodrug that is activated by CYP2C19
-
Why should you not use Clopidegrel with a PPI?
PPIs are CYP2C19 inhibitors
-
What percent of people are homogenous for CYP2C9 low activity?
2-10%
-
What drugs are involved in CYP2C9 metabolism?
Warfarin and Losartin
-
What enzymes are involved in Warfarin metabolism?
2C9 and KVOR
-
Why does the package labeling for Warfarin not say to screen for CYP2C9 or KVOR metabolism rates?
- We have other drugs that can be used
- If a person is producing unpredictable results, we just switch them to Rivaroxaban or Dabigatrin instead of screening
-
What are the main areas of treatment where pharmacogenomics has the greatest impact?
- Psychology
- Infectious disease
- Oncology
-
What gene polymorphism affects Statin myopathy risk?
- SNPs located within SLCO1B1 on chromosome 12 = increased myopathy
- Mutations in the Low density lipoprotein receptor
-
If a patient is not responding to a Hep C treatment, what genetic components may be interfereing?
- Peg-interferon and ribavirin metabolism is effected by:
- IFNL3 (IL28B) genotype predicts response
-
What was the first available device for testing enzyme status and how does it work?
- Roche AmpliChip P450 Test
- Measures CYP2D6 and CYP2C19 genotype from DNA extracted from a whole blood
- Categorizes patients as PM, IM, EM or UM
|
|
