Lecture 7: Metabolism Flashcards
CYP450 induction mechanism
-drugs bind to CYP TFs
-increase transcription
-increase CYP450
-increase metabolism
induction cross-talk
-many substrates can turn on different CYPs
-alter metabolism of a LOT of drugs
Inducers cause a wider array of drug interactions than inhibitors
-reacts with PXR
-doesnt have to interact with CYP directly
Autoinduction
-inducer [drug] can activate own metabolism
-concentration decreases with same dose
Consequences of metabolisms
- active to inactive
- inactive to active
- active to reactive
CYP1A1/2 substrates
-PAHs
-arylamines
-nitrosamines
CYP1A1/2
-planar binding site
-only binds flat (planar) molecules
CYP2 family
-2A6
-2B6
-2C9/8
-lots more substrates
CYP2C subfamily
-metabolizes 25% of drugs
-bigger binding pocket
-CYP2C9 most important
CYP2D6
-metabolizes 20% drugs
-small amounts in body
-weakly inducible
CYP2D6 metabolism
-lipophilic amines
-ion-pair interactions
-cardiovascular drugs, B blockers, antipsychotics, SSRIs etc
CYP2D6 inhibition
-fluoxetine
-quinidine
-bupropion
CYP3A4
-biggEST pocket
-inducer increases metabolism of ALL substrates
-inhibitor will not compete with all substrates
CYP3A4
-50% of drugs
-low specificity