p450 reactions Flashcards
AUC and steady state concentrations are dependent only on what
the enzymes involved
phases of liver metabolism
- phase 0 - uptake to hepatocyte
- phase 1 - oxidation, reduction, hydrolysis
- phase 2 - glucuronidation, methylate, acetylate
- phase 3 - excrete into blood
pharmacodynamics definition
what drugs do to the body
metabolism phase 1 reactions
oxidation
reduction
hydrolysis
metabolism phase 2 reactions
glucuronide conjugation
methylation
acetylation
metabolic processes affected my gene mutations
metabolism
transport
PD
5 functions of P450’s
- metabolize drugs
- synthesize steroid hormones/bile acid
- synthesize prostaglandin, thromboxane, leukotriene
- metabolize fat-soluble vitamins
- synthesize vitamin D3
where are P450s
- ER of cells
- mainly in liver
- gut, lung, skin, kidney
most common P450s
1A2 2C9/2C19 2D6 2E1 3A4
solute carrier transporters typically go which direction
extracellular to intra (influx transport)
ATP binding cassette transporters go which direction
efflux
example of ATP binding cassette transporter
P-glycoprotein
P-glycoprotein drug importance when deficient
- tumor drug resistance
- reduction DOAC effect
power source of P-gp
ATP
reversible inhibition
temporary association with CYP
irreversible inhibition
suicide substrate that covalently binds to enzyme
types of reversible inhibition
competitive
noncompetitive
uncompetitive
noncompetitive inhibition
binds to a non-active site, making enzyme not function
uncompetitive inhibition
binds to enzyme-substrate complex
degree of inhibition depends on
affinity to enzyme
strong inhibitor classification
> 5 fold increase in plasma AUC or >80% reduction in clearance
moderate inhibitor classification
> 2 fold increase in plasma AUC or 50-80% reduction in clearance
weak inhibitor classification
> 1.25 and <2 fold increase in plasma AUC or 20-50% reduction in clearance
when does inhibition occur
- within 24 hours
- can be concentration-dependent
- clinical effect may take a couple days
inducers function
-form more CYP enzymes or transporters via transcription
rifampin induces
2C9 2C19 3A4 P-gp OATP
ritonavir induces
3A4
P-gp
OATP
how long to see induction effects
3-5 days
things that cause autoinduction
carbamazepine
smoke
alcohol
strong inducer classification
> 80 decrease in AUC
moderate inducer classification
50-80% decrease in AUC
weak inducer classification
20-50% decrease in AUC
examples of prodrugs
cyclophosphamide
codeine
hydrocodone
1A2 substrates
caffeine clozapine duloxetine naproxen theophylline cyclobenzaprine
1A2 inhibitors
cimetidine
ciprofloxacin
fluvoxamine
amiodarone
1A2 inducers
charbroil
tobacco
rifampin
2C9 substrates
NSAIDS fluoxetine losartan glipizide phenytoin warfarin
2C9 inhibitors
amiodarone fluconazole (Strong) isoniazide metronidazole paroxetine Sulfamethoxazole voriconazole
2C9 inducers
barbiturates
rifampin
SJW
2C19 substrates
amitriptyline cyclophosphamide clopidogrel diazepam lansoprazole omeprazole phenytoin
2C19 inhibitors
cimetidine ketoconazole fluoxetine fluvoxamine lansoprazole omeprazole
2C19 inducers
efavirenz
rifampin
ritonavir
SJW
2D6 substrates
SGA's codein duloxetine metoprolol paroxetine tramadol tamoxifen
2D6 inhibitors
bupropion (S) cimetidine duloxetine fluoxetine (S) paroxetine (S) quinidine (S) ritonavir (S) methadone
2D6 inducers
none, its resistant
2E1 substrates
APAP
acute alcohol
2E1 inhibitors
disulfiram
2E1 inducers
chronical alcohol
3A4 substrates
macrolides benzos immune modulators HIV protease inhibs CCB statins DOACs methadone
3A4 inhibitors
amiodarone nefazodone (S) CCBs grapefruit ketoconazole (S) clarithromycin (S) erythromycin cimetidine
3A4 inducers
carbamazepine phenobarbital phenytoin rifabutin rifampin SJW
P-gp substrates
apixaban rivaroxaban dabigatran digoxin losartan
P-gp inhibitors
amiodarone
diltiazem
carvedilol
verapamil
P-gp inducer
amiodarone
fluoxetine primarily inhibits
2C19
2D6
fluvoxamine inhibits
1A2
2C19
2D6
3A4
paroxetine primarily inhibits
2D6
3A4
citalopram inhibits
barely any, very little DDI
2 herbal interactions to know about
SJW induce 3A4
Dill may inhibit 3A4
high risk drug interactions
- narrow therapeutic window drugs
- no alternate elimination pathways
- no alternatives
- dose adjustments not known
top 4 drug interactions to be aware of
- sildenafil + isosorbide mononitrate (nitrate)
- potassium and spironolactone
- warfarin and basically anything
- tyrosine kinase inhibs + 3A4 inhib/QT drugs/P-gp inhib/PPIs
rate of DDIs increase with
- # of prescribed meds
- # of OTC meds
- increased age age
