Gurley Feb 5 pt.1 (CYP3A4) Flashcards
what is the most abundant Cytochrome in humans?
CYP3A4
where is CYP3A4 in highest concentrations?
what is the efflux pump co-expressed with it in these locations?
liver and small intestines
P-glycoprotein (a.k.a. ABCB1)
about what percent of prescription drugs are metabolized by CYP3A4
50%
what are two features noted with genetic polymorphisms in CYP3A4
- large intersubject variability
2. don’t have a major effect on its metabolism
what has the least allelic varience 3A4 or 3A5
3A4 (least amount of allelic varience out of all CYPs)
what type of drugs are effected the most by changes in CYP3A4?
drugs with a narrow therapeutic window
true/ false:
A drug can be both a substrate and an inhibitor?
true
what two benzodiazipines are not 3A4 substrates
TEST Q according to gurley
oxazepam and lorazepam
what are the general drug ‘categories’ of CYP3A4 substrates (6 total; exceptions not included)?
- azole antifungals
- benzodiazepines
- Ca channel blockers
- HMG-co reductase inhibitors
- macrolide antibiotics
- steroids
what HMG-co reductase inhibitor is not a CYP3A4 substrate?
pravastatin
what macrolide antibiotic is not a CYP3A4 substrate
azithromycin
list the CYP3A4 inhibitors noted in class
- troleandomycin
- ritonavir
- itraconazole
- clarithromycin
- ketoconazole
- erythromycin
what is probably the most potent CYP3A4 inducer
St. John’s wart
what are the CYP3A4 inducers (10 total)
- carbamazepine
- dexamethasone
- efavirenz
- nevirapine
- phenobarbital
- phenytoin
- primidone
- rifampin
- rifabutin
10 st. johns wort
what is probably the most potent CYP3A4 inhibitor
ritonavir
- what immunosuppressant given for transplants taken in conjunction with Azole antifungals inhibits CYP3A4?
- what does this often lead to?
- why do some doctors do this intentionally?
- cyclosporine
- nephrotoxicity (from cyclosporine toxicity)
- reduce cyclosporine dose needed (very expensive drug)
Erythromycin, a potent CYP3A4 inhibitor taken in conjunction with what antihistamine can lead to Torsades?
terfenadine
what orphan nuclear receptor is most commonly activated by induction of CYP3A4?
SXR (steroid-xenobiotic receptor)
activation of SXR does what
induces overexpression of CYP3A4
the activation of transcription factors such as CAR, SXR and PXR requires what 3 things
- binding of ligands
- formation of heterodimers
- heterodimer binding to XRE (xenobiotic response elements)
what is considered ‘the quintessential substrate’ for 3A4?
midazolam
what is the overall average increase in CYP3A4 if a patient is given St. Johns Wort? (seen in studies with midazolam plasma ratios )
98%
what is shown to be the most potent ligand for PXR?
hyperphin (sp?)
St. John’s wort and rifampin induce CYP3A4 and what else?
where
p-glycoprotein (P-gp)
in the small intestine
