16 Pharmacogenomics in Viral Infections Flashcards
(23 cards)
What part of the genome contains most of the genetic mutations?
Promoter region and Introns
What is usually done in Phase 1 Metabolism?
Done through CYP enzymes
What is usually done in Phase 2 Metabolism?
Done through UGTs, Sulfation, etc
What are the biggest inhibitors of OATP1B1?
Cyclosporin, Rifamycin, Rifampin
What class of drugs commonly inhibits OATP1B1?
Statins (Atorva > Lova > Simva > Rosuva
What do CYP 2B6 SNPs predict?
Efavirenz and Nevirapine plasma levels
What do CYP 2C19 SNPs predict?
Predicts Nelfinavir plasma levels
What does HLA predict?
Nevirapine rash and/or liver toxicity
What do UGT1A1 variants predict?
Atazanavir and Indinavir bilirubin levels
What does APOC predict?
Plasma lipids on protease inhibitors
What does SLCO1B1 predict?
Lopinavir plasma levels
What is UDP Glucuronyl Transferase 1A1 responsible for?
Responsible for Gilbert’s Bilirubinemia. Absent in ~15% of Caucasians (> 50% in AA and Hispanics). Decreased activity in hypoglycemic and malnourished conditions, so Gilbert’s hyperbilirubinemia is “revealed” by these conditions
Which CYP enzyme is most active in fetus?
CYP 3A7, gets replaced by CYP 3A4 after birth
What are the major Pgp substrates?
Digoxin. Verapamil. Fexofenadine (Allegra). HIV Protease Inhibitors. Erythromycin
What are the major Pgp inhibitors?
Macrolides (except Azithromycin). Cyclosporin. Itraconazole, Ketoconazole
What are the major Pgp inducers?
Rifampin and St. Johns Wort
Which genotype for MDR-1 has the best CD4 count response with Nelfinavir?
TT > CT > CC
What MDR-1 genotype do AA have?
68% have CC. This causes them to have very high plasma concentrations –> CNS ADRs. Low intracellular levels, poor outcomes. CC genotype also causes Hepatotoxicity with Nevirapine treatment
How does ethnicity effect Efavirenz?
Decreased EFV clearance associated with AA race. EFV concentrations not associated with CNS virologic suppression or CNS toxicity. Trend toward increased EFV concentration and increased discontinuation
When it comes to CYP 2B6 genotype and Efavirenz, what do AAs have?
AAs have TT > GT > GG, which causes very high Efavirenz plasma levels
Which transports do RTV block?
MRPs and Pgp
How can adding RTV and TFV cause cellular death?
TFV is brought into the cell through OAT-1, it would then usually be pumped into the lumen (urine flow) through MRPs and Pgp. RTV blocks these pumps, causing TFV –> TFV-MP –> TFV-DP, which gets into the mitochondria and causes damage
Which genotype of IL28 has the best response to therapy?
CC
