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alterations in the DNA (genetic) code occurring <1% of the time in the population
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?
What enzymes mediate Phase I Metabolism and what is their usual mechanism?
- Cytochrome P-450 (CYP)
What enzymes mediate Phase II Metabolizing Enzymes and what is their usual mechanism?
- Glutathione S-transferase
Which enzyme is going to be the most common isoenzyme associated with polymorphisms?
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?
What drugs are metabolized by CYP2C9?
What are populations of poor CYP2C19 metabolizers?
What drugs are metabolized by CYP2C19?
- Clopidegrel (Plavix)
What are populations of poor Dihydropyrimidine dehydrogenase metabolizers?
1% heterozygous of entire population
What drugs are metabolized by Dihydropyrimidine dehydrogenase?
What are populations of poor Uridine diphosphate-glucuronosyltransferase 1A1 metabolizers?
10% among whites
What drugs are metabolized by Uridine diphosphate-glucuronosyltransferase 1A1?
What are populations of poor Thiopurine S-methyltransferase metabolizers?
- ~ 1/300 whites
- ~1/2500 Asians
What drugs are metabolized by Thiopurine S-methyltransferase?
Which enzyme has the most well characterized polymorphisms?
What percent of drugs does CYP2D6 meatabolize?
What are general drug types are CYP2D6 substrates?
- 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?
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?
What are the main drugs involved in CYP2C19 metabolism?
- Omeprazole - PPIs
CYP2C19 has what effect on PPIs, like Omeprazole?
Inactivates = PM have better cure rates than UM
How many different variants of CYP2C19 are there?
Why is it hard to tell what type of CYP2C19 metabolizer a person is?
25 different variants
What enzyme mainly metabolizes Clopidigrel?
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?
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?
- Infectious disease
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