PHARM: Precision Medicine: Clinical Pharmacogenomics Flashcards
What is precision medicine?
A form of medicine that uses info about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease
What gene variant is responsible for variation in susceptibility to doxorubicin-induced cardiotoxicity in breast cancer treatment?
G671V in ABCC1 transporter
What is pharmacogenomics?
The science of determining how genetic variability influences physiological response to drugs, from absorption and metabolism to pharmacological action and therapeutic effect
What are the two broad classes of genetic variance?
Germline variance (changes in inherited DNA) and Somatic variance (changes that occurred w/in the individual
What is the target of Gleevec? What is it used to treat?
Targeted against the mutant BCR-Abl tyrosine kinase protein found in chronic myelogenous leukemia
What CYP450 is affected by St. John’s Wort and how does this affect metabolism of drugs metabolized by the enzyme?
St. John’s Wort induces CYP3A4 and can cause rapid metabolism of drugs cleared by the enzyme, decreasing their effectiveness
What CYP450 is affected by grapefruit juice and how does this affect metabolism of drugs metabolized by the enzyme?
CYP3A4 is inhibited by grapefruit juice causing the substrates of the enzyme not to be metabolized, increasing exposure to the drug and causing potentially dangerous side effects
How is warfarin primarily metabolized and how does it exert its anticoagulant effect?
Metabolized primarily via CYP2C9 and exerts its effect by inhibiting vitamin K epoxide reductase complex, subunit 1 (VKORC1)
What polymorphisms affect Warfarin metabolism and how?
CYP2C91 confers normal warfarin metabolism, CYP2C92 reduces metabolsim by 30%, CYP2C9*3 reduces metabolism by 90%, and VKORC1 SNP 1639 produces leess VKORC1
How is clopidogrel metabolized and how does it exert its function?
Clopidogrel is a prodrug that is activated by CYP2C19 and irreversibly inhibits platelet ADP receptor P2RY12
What polymorphisms affect clopidogrel metabolism and how?
CYP2C191 confers normal metabolsim, CYP2C192 and 3 confer poor metabolism, and CYP2C1917 confers hyper metabolism
How does metformin work? What effects does it elicit?
Metformin acts in the liver to activate AMPK which decreases blood glucose, LDL, and triglycerides and increases insulin sensitivity
What SNPs are relevant to Metformin metabolism/ efficacy?
SNP rs2289669 G>A in the SLC47A1/MATE1 transporter (transports metformin out of liver) inactivates the transporter, keeping metformin in the liver longer and increasing its effectiveness
How is 5-fluorouracil dosed? How does it act? How is it metaboized?
Dosed as a prodrug that is converted to 5-fluoro-2-deoxyuridine monophosphate to inhibit thymidylate synthase. More than 80% of 5-FU is inactivated by dihydropyrimidine dehydrogenase (DPD)
What genetic variants are responsible for variance in 5-FU efficacy?
Patients with low DPD activity cannot efficiently inactivate 5-FU, causing accumulation of 5-FdUMP and potentially dangerous side effects; Patients with tandem repeats in the promoter of the thymidylate synthase are chemoresistant to inhibition by 5-FU therapy
