Kruse DSA: Pharmacogenetics Flashcards
CYP2D6 importance
hepatic metabolism of 20% of commonly used drugs
-polymorph importance in codeine –>morphine
-death in ultrarapid metabolizers
CYP2C19 importance
small number of very important drugs metabolized by this enzyme
- diazepam, clopidogrel, propranolol, omeprazole, tricyclic antidepressants (DC POT)
- reduced enzyme efficacy with clopidogrel = lower active metabolite = increased risk of clots
- GOF = increased active metabolite = ncreased bleeding
dihydropyrimidine dehydrogenase (DPD) importance
clears 5-FU which is a first line prodrug for the treatment of colorectal cancer
- capecitabine and tegafur are prodrugs that are converted ijn body to 5-FU
- in body 5-FU is converted to cytoxoic 5-FUMP and 5-FdUMP
- nonfunctional DYPD gene = increased toxicity
CYP2C9 and VCORC1 importance
- responsible for inactivation of S-warfarin
- mutations in VCORC1 can lead to spontaneous bleeding disorders
- decrease in either leads to increase warfarin and increased bleeding
UGT1A1 importance
phase II enzyme
- clears SN-38, the bioactive metabolite of irinotecan, cytotoxic agent used in treatment of colorectal cancer
- reduced fnct polymorph =irinotecan indcued BM depression and diarrhea
TPMT importance
inactivates chemotherapeutic purine derivatives like 6-MP, azathioprine and 6-TG
-reduced fnct polymorph = altereted therapeutic efficacy and altered toxicity
G6PD polymorph can lead to resistance against
but also increase
malaria
increase suscept to hemolysis
transporters
SLO1BI and OATP
SLCO1B1 gene codes for OATP
- transports drugs and endogenous compounds from blood into hepatocytes
- substrates = statins, and methotrexate
- reduced fnct results in elevated concentration of some statins (especially simvastatin) and increases risk of skeletal m myopathy
transporters P-glycoprotein
found in blood tissue interfaces
- formally called MDR1
- expells cytotoxic drugs from resistant cancer cells
- ABCB1 gene
