Pharmacogenomics Flashcards
PGx
Pharmacogenomics: study of variation of DNA and RNA characteristics related to drug response
PGt
Pharmacogenetics: study of variation of DNA sequence related to drug response
What is the MOA of warfarin/ coumadin
Warfarin (R/S) —> inhibits vitamin K epoxide reductase (VKOR) —> cannot convert Vitamin K to Vitamin k (H2) —> gamma-glutamyl-carboxylase calumenin cannot convert vitKH2 back to vitK which activates coagulation factors (2, 7, 9, 10) —> no coagulation
Gene variants affecting warfarin MOA
- CYP2C9 gene —> CYP2C9*2 and *3
- VKORC1 gene —> c-16339G>A (promoter mutation)
** Footnote
CYP2C9 variants —> less functional cytochrome P450, slower metabolism of warfarin S
VKOR variants —> less VKOR, more susceptible to low doses of warfarin
What does CYP2C9 gene do
Encodes for cytochrome P450 to metabolise warfarin S
Factors affecting dose response to warfarin
- Age
- Ethnicity (dose requirements: asians<causcassians< african americans
- diet rich in vitamin K?
- drug-drug/supplement interaction
- health conditions
MOA of gefitinib
Gefitinib prevents the autophosphorylation of EGFR thus decreases cellular proliferation response
Gene variants affecting gefitinib MOA
EGFR variants:
- L858R
- L858R/T790M
NSCLC variants:
- KRAS
- PTEN loss
- PI3KCA
- BRAF
**Footnote
L858R: more susceptible to gefitinib treatment in cancer patients due to lower Kd
T790M is a secondary mutation
L858R/T790M: gefitinib resistance due to high Kd
KRAS is an oncogene
PTEN is a tumor suppressor gene
MOA of irinotecan
- irinotecan inhibits topoisomerase I -> cancer cell death
- glucuronidation metabolic pathway: irinotecan is metabolised in the liver to give SN-38 active metabolite —> inactivated by UGT into SN-38G (G=glucuronide)
Variants affecting irinotecan MOA
UGT1A1 gene
- UGT1A128
- UGT1A16
Footnote:
UGT1A128 —> longer TATA repeats: lower TF binding efficiency —> less UGT to inactivate SN-38
UGT1A16 —> decreased UGT activity
