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55 Cards in this Set
- Front
- Back
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What is the most widely studied enzyme in relation to polymorphisms? |
CYP2D6 |
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What is CYP2D6 do? |
Involved in the elimination of ~25% of drugs including lipphilic bases such as beta-blockers, antidepressants, neuroleptics, antiarrhythmics, and opioids |
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T/F All drugs metabolized by CYP2D6 require genotyping/phenotyping |
False, not all drugs metabolized by CYP2D6 require genotyping/phenotyping |
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What are the normal alleles for CYP2D6 (extensive metabolism) |
*1, *2, and *39 (wild type) are extensive metabolizers |
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What are the alleles for intermediate metabolizer in CYP2D6? |
*10, *17, *28, *41 are intermediate metabolizers |
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What are the alleles for poor metabolizers in CYP2D6? |
*3, *4, *5 are poor metabolizers |
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What leads to ultra rapid metabolizers in CYP2D6? |
Gene multiplication/duplication lead to UM phenotype
CYP2D6*17x2 and CYP2D6*41x2 |
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Phenotyping of what drug can save patients from toxicity (such as hepatotoxicity and peripheral neuropathy)? |
Perhexiline phenotyping can save patients from toxicity |
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What do we need to know about Tamoxifen in relation to polymorphism in CYPD6? |
Poor metabolizers are at an increased risk for treatment failure with TAMOXIFEN and genotyping prior to initiating therapy may be of benefit |
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What drugs inhibit CYP2D6? |
SSRI |
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What is the must abundant enzymes of the CYP2C enzymes? |
CYP2C9 |
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What drugs do CYP2C9 metabolize? |
Coumarins, sulfonylureas, angiotensin II blockers, phenytoin, NSAID |
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What alleles reduce CYP2C9 activity, why does it reduce activity? |
Alleles *2 and *3 reduce CYP2C9 activity
Due to SNPs resulting in amino acid change at residues 144 (430C>T, arg to cys) and 359(1075A>C, ile to leu) |
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For CYP2C9 what alles are poor metabolizers and intermediate metabolizers?
What drugs will this effect? |
*3/*3 = poor metabolizer
*2/*2 and *2/*3 are poor or intermediate metabolizers
Warfarin and Phenytoin |
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What does CYP2C19 do? |
CYP2C19 metabolizes S-mephenytoin, omeprazole, and proguanil |
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What is CYP2C19 also known as historically? |
S-Mephenytoin hydroxylase |
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What alleles inactivate CYP2C19? activate? |
*2 *3 and *4 inactivate CYP2C19
*17 activates (ultra rapid metabolizer) |
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For CYP2C19 what drugs are important to run pharmacogenomic tests on? |
Omeprazole, lansoprazole, and clopidogrel |
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What is DPD and what does it do? |
DPD = Dihydropyrimidine dehydrogenase
Deactivates 5-FU. Metabolizes pyrimidine analogs (thymine and uracil) including the antineoplastic agent 5-fluorouracil |
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What would a deficiency in DPD mean? |
Tremendouly increase the blood concentration of 5-fluorouracil's active form to a toxic level through the salvage pathway |
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How can we determine if a patient has DPD deficiency? |
The liver and peripheral blood mononuclear (PBM) cells express DPD and thus phenotyping by determining PBM cell DPD activity |
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What drug is contrainindicated in patients with known DPD deficiency? |
Capecitabine (Xeloda) converted in vivo to 5-FU |
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What is the most clinically significant cause of DPD deficiency? |
DPYD2A allele that involves G>A point mutation |
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What is N-acetyltransferase type 2 (NAT2) involved in? |
Acetylation of isoniazid, hydralazine, procainamide, dapsone, and some sulfonamide derivatives |
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What percentage of african-americans and caucasians are slow acetylators? |
40-70% of african americans and caucasians are slow acetylators |
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What are the common slow acetylating phenotypes in caucasian and asian populations? How many nucelotides are substituted? |
C481T, G590A, and G857A are the most common slow acetylating phenotypes in caucasian and asian populations
1-4 nucleotides are substituted |
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What alleles are fast acetylators? |
*4/*4 are fast acetylators |
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What drugs should be genotype for in relation to acetylation? |
Hydralazine and isoniazid therapy to avoid increased toxicity in slow acetylators and reduced efficacy in fast acetylators |
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What enzymes deactivate Azathioprine and thioguanine metabolites? |
Azathioprine --> 6-MP --xanthine--> 6 thiouric acid
T-IMP/T-GMP/6-MP/Thioguanine --TPMT--> 6-methylmercaptopurine |
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What does TPMT deficiency lead to? What alleles are responsible? |
Increased production of active nucleotides and development of myelosupression and hepatotoxicity
alleles *2, *3A, and *3C are associated with TPMT deficiency
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Where is TPMT usually present? |
Most active in RBC, but present in many tissues |
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What is UGT1A1 also called? What does it do? |
Uridine diphosphate glucuronosltransferase 1A1
Deactivates irinotecan (an anticancer agent) |
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What is irinotecan? |
An anticancer agent.
A prodrug that is activated by esterase hydrolysis to 7-ethyl-10-hydroxycamptothecin (SN-38) then glucoronidated by UGT1A1 (inactivation) |
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What happens in patients with defective UGT1A1? What gene? |
Defective glucoronidation (no inactivation of SN-38).
Has a variant gene UGT1A1*28 (TA)7TAA instead of the natural (TA)6TAA.
Basically the defective gene has an extra thymine in the promoter TATA section that results in reduced enzyme activity |
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What does the FDA recommend before initiating irinotecan therapy? |
Testing of the patient's UGT1A1 status so we can get the right dose. |
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Know the enzymes for the following drugs!
Azathioprine, 6-MP
Warfarin, Phenytoin, Tobutamide, Losartan
Omeprazole, Lansoprazole
Perhexiline, Codeine, Metoprolol
Efavirenz
5-FU
Hydralazine
Irinotecan |
Azathioprine, 6-MP = TPMT Warfarin, Phenytoin, Tobutamide, Losartan = CYP2C9 Omeprazole/Lansoprazole = CYP2C19 Perhexiline/Codeine/Metoprolol = CYP2D6 Efavirenz = CYP2B6 5-FU = DPD Hydralazine = NAT2 Irinotecan = UGT1A1 |
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List the drugs that prefer phenotyping tests |
Azathioprine/6-MP Perhexiline 5-FU (both geno and pheno) |
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List the drugs that prefer genotyping tests |
Warfarin/Phenytoin/Tobutamide/Losartan Omeprazole/Lansoprazole Codeine Metoprolol Efavirenz 5-FU (both pheno and geno) Hydralazine Irinotecan |
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What is the result of the allele CYP2C9*2? |
CYP2C9 metabolizes warfarin
CYP2C9*2, 430C>T, which changes arg to cysteine at codon 144. Result is a 30-40% reduction in S-warfarin (active form) metabolism
The active form isn't getting metabolized! CYP2C9*2 allele means you should lower the dose |
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What allele in warfarin results in PM or IM? The result? |
CYP2C9*3 = poor metabolizers or intermediate metabolizers. Have a higher s-warfarin (active) blood concentration, resulting in severe warfarin toxicity (increased bleeding risk) |
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List the dosages of warfarin in patients with different CYP2C9 alleles |
*3 is the worst metabolizer, *1 is the best metabolizer
*1/*1 = 5.63 *1/*2 = 4.88 *1/*3 = 3.32 *2/*2 = 4.07 *2/*3 = 2/34 *3/*3 = 1.60 |
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What enzyme metabolizes Tamoxifen? What is the result of a polymorphism of this enzyme? |
CYP2D6
Genetic polymorphism results in changes in serum concentration of tamoxifen's active metabolite (endoxifen)
Basically, tamoxifen needs to be metabolized to endoxifen to be more potent. This enzyme is needed! |
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How much more potent is endoxifen in comparison to tamoxifen? |
100x more potent |
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What alleles result in ultra rapid metabolizing of tamoxifen? Extensive? Intermediate? Poor?
What can happen if this enzyme is poor? |
UM = CYP2D6*1/*1xN (gene duplication) EM = CYP2D6*1/*1 IM = CYP2D6*3/*17 PM = CYP2D6*3/*3
Breast cancer patients with IM or PMK phenotypes will exhibit lower survival rates compared to UM and EM.
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What are some examples of thiopurines? |
6-mercaptopurine, azathioprine, and thioguanine |
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What enzymes effect thiopurines, what is the result? |
TPMT metabolizes thiopurines.
This increases active metabolites, leads to toxicity |
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What are the most frequent TPMT allele variants? |
TPMT*2 (238G>C) ala to pro *3 (460G>A and 719A>G) ala to thr and tyr to cys *3C (719A>G) tyr to cys |
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FDA recommends what in regards to thiopurine? |
Reduced or alternative dosages in patients carrying a nonfunctional TPMT allele.
Suggested alternative therapy in homozygous nonfunctional TPMT alleles |
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What is irinotecan? |
anticancer prodrug.
SN-38 is it's active form
Inactivated by UGT1A1 |
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What enzymes activate irinotecan? |
Carboxylesterases or butrylesterases concvert irinotecan to SN-38 (active)
It is then deactivated by UGT1A1 |
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If you have low activity of UGT1A1 what can happen? |
Increased serum concentration of the active metabolite (SN-38) since it's not being deactivated.
Increased adverse effects including neutropenia |
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What alleles of UGT1A1 result in a higher risk of adverse effects? |
UGT1A1*28/*28 results in lowered enzyme production and activity. Results in significantly higher risk for adverse events compared with patients carrying UGT1A1*1/*1 (wild type)
*1/*1 = good *28/*28 = bad |
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What does the FDA recommend in regards to irinotecan? |
If patient has UGT1A1*28/*28 (lowered enzyme production/activity), reduce the dose. |
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What is clopidogrel? What enzyme metabolizes it? The result? |
A platelet inhibitor, also a prodrug. COOH is the active metabolite.
Metabolized by CYP2C19 is involved in both the intermediate and active metabolite steps.
CYP3A4 is involved in the 2nd step to form COOH in the active metabolite |
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In clopidogrel, what alleles result in PM? What happens if this is the case? |
CYP2C19*2 or *3 = PM. People with this allele have higher rate of cardiovascular events than patients carrying wild type genes due to significantly lower serum levels of active metabolite resulting in diminished platelet inhibition |
