Genetic Variability Flashcards
How are drugs metabolized by CYPs?
- Phase 1 of drug metabolism results in the addition of a hydroxyl group to the molecule
- Phase 2 is the functionalization of hydroxyl group by a sugar or acetyl group, which increases the solubility allowing it to be excreted.
Warfarin
Aka Coumadin
- Blood thinner
- Used in cases where patients are susceptible to thrombosis, embolism, valve prothesis, recurrent stroke, deep vein thrombosis, and pulmonary embolism.
- Modified or metabolized by CYP2C9
PT or Prothrombin test
- PT of standard blood is around 11-13 seconds
- Warfarin increases the amount of time it takes blood to clot since it is a blood thinner
INR ratio
- INR= PT (obs in patient)/ PT (normal standard)
- INR of 1 means a patient’s blood takes the normal amount of time to clot.
- INR > 1 means it takes patient’s blood longer to clot than standard. Warfarrin increases INR in patients since it takes a longer time for blood to clot when Warfarrin is administered.
What is CYP?
- CYPs are cytochrome p450s which play a role in drug metabolism.
- Pink part of CYP is a heme that is covered with a flap (beta hairpin).
- The flap opens up and allows drug to flow into the CYP.
- Once drug is inside, the flap closes holding drug against heme which them chemically modifies drug.
Processing of Tylenol
Two steps to processing Tylenol
- Acetominophen is processed to N-Acetyle-p-benzoquinone imine slowly by CYP3A4 (primary CYP although 9 other CYPs are also capable of doing this processing).
- Benzoquinone is toxic in cells
- Liver is then taking benzoquinone and further modifying it so that it can be excreted.
- If you have high dose of acetaminophen, overdose can occur because the reaction is being pushed to the right such that more benzoquinone is being made and then it has to be further modified by liver to be excreted.
- Processing of acetyminophen by CYP3A4 takes hours
- Further modification of benzoquinone takes days
Warfarrin sensitivity
- If you have an allele of CYP2C9 such that there is SNP in the gene of the CYP2C9 gene resulting in decreased activity of the CYP2C9, the enzyme will not be able to hydroxylate Warfarrin as quickly so that liver can further modify and excrete the Warfarrin.
- If this is the case, Warfarrin stays in the body for a longer period of time.
- Therefore, individuals with this allele will not need as high of a dosage of Warfarrin and therefore are sensitive to the drug. Only a small dosage is required to have the desired effect.
Warfarrin Tolerance
- If you have an allele of CYP2C9 such that there is a SNP in the gene of CYP2C9 resulting in increased activity of the CYP2C9 enzyme, Warfarrin will be rapidly hydroxylated allow liver to then modify and excrete it.
- If this is the case, Warfarrin is cleared from the body faster.
- Therefore, individuals with this allele will need a higher dosage of the drug because they are tolerant to the drug. A higher dosage is required to have the desired effect.
If you have an allele that increases functionality of CYP enzyme
- Homozygotes for the allele will be ultrafast metabolizers (tolerant)
- Heterozygotes for the allele will be intermediate metabolizers
- Homozygotes without the allele will be poor metabolizers (sensitive)
If you have an allele that decreases functionality of the CYP enzyme
- Homozygotes for the allele will be poor metabolizers (sensitive)
- Heterozygotes for the allele will be intermediate metabolizers
- Homozgyotes without the allele will be ultrafast metabolizers (tolerant).
VKORC1 without presence of Warfarrin
- Vitamin K (oxidized) binds to VKORC1
- Vitamin K goes from oxidized to reduced/active form
- Active form of Vitamin K activates GGCX
- GGCX processes and activates clotting factors.
VKORC1 in presence of Warfarrin
- S-Warfarin binds to VKORC1 preventing Vitamin K oxidized form to bind.
- Vitamin K does not go from oxidized to reduced/active form
- GGCX is not activated and therefore does not activate clotting factors
VKORC1 and Warfarrin sensitivity
If an allele results in a mutation in VKORC1 that increases its affinity for Warfarin, the individual is more sensitive to Warfarin because the target has a tighter affinity for the drug so less of it is needed to have the same effect.
VKORC1 and Warfarrin tolerence
If an allele results in a mutation in VKORC1 that decreases its affinity for Warfarin, the individual is more tolerant to Warfarin because the target has a lower affinity so more of the drug is needed to have the same effect.
