Oral F + first pass extraction Flashcards
(21 cards)
What factors impact F
F= FA x (1-Ei) x (1-Eh)
FA: fraction of admin dose that is not destroyed in gut or lost in feces
—- this is the % of dose that can actually be taken in through gut (get to body)
Ei: portion of drug that is extracted/eliminated in intestines
Eh: portion of drug extracted by first pass metabolism (hepatic)
— high for I or H: indicates poor F even if FA is high because both prevent drug getting to systemic circulation
T or F: we can measure intestinal extraction
F — only predict based on knowing what P450 metabolize drugs
—- main enzyme found in enterocytes: CYP3A4
—— if not metabolized by CYP3A4: likely to not be extracted in intestines/eliminated here
How does grapefruit juice impact extraction
inhibits specifically CYP3A4 in intestines (not liver)
—- has high levels of furanocoumarins that inhibit CYP3A4 in I
- decrease extraction/elimination of these drugs at intestine (decrease Ei)
more drug goes to liver + increase in peak plasma conc (no change to t1/2, Cl, or V)
T or F: hepatic extraction can occur with any P450 enzymes
T- can be any of them
- all drugs that are metabolized by liver can never have 100% F
T or F: there is a correlation bw CYP3A4 extraction in intestine + liver
F - some have high I and low liver, while others have opposite
——- can never know though if extraction happening at liver or intestine + what degree
— if sub for enzyme that isn’t CYP3A4: extraction likely not intestinal
Impact of high Eh on F
low F : therefore will need to increase dose to reach IV plasma C
— sometimes so low it can’t be given orally
Variable F: if high Eh, there will be more variation in F bw people
—-if changes in A or Ei, will have big impact on C differences bw people (ex// 700X)
Effect of RoA on first pass metabolism
can avoid it largely if take via buccal, sublingual or rectally
— can increase F and avoid first pass metabolism
T or F: disease states can change E
T- disease states or DIs can change E
— does depend on if drug has high or low E to start
— if increase E: decreases F
—- decrease E: increase F
What factors impact the livers ability to extract drugs (E)
Clint: inherent ability to clear drug
Q: delivery of drug
fu
—- changes in these could impact E and F
T or F: can calculate Clint from measured AUC after dose
T
Cl= F* dose/AUC
Clint= Cl/F
Clint= dose/AuC = Cl/F
poorly extracted drugs have ——- F
good F
- are not impacted significantly be changes in Clint, Q or fu
** aka extraction is so low already, can’t really decrease much more or increase much more
Poor E: what happens if increase Clint or Q
increase Clint —- increase Cl
— slight increase in E + slight decrease in F
Increase Q: no change in Cl, slight decrease in E + slight increase in F
** neither of these are significant
Impact of increase in Clint on AUC and t1/2 of low E drug
increase CLint —- increase Cl
F doesnt change but AUC will decrease (bc Cl increases)
— decrease in plasma C
t1/2 decreases/faster due to changes in Cl (steeper slope)
no change in V
Impact of increasing Q on AUC of poor E drug
no impact: doesn’t change CL —- no change in AUC or t1/2
High E drugs have —— F
poor F
— therefore changes in CLint or Q will change E + F more
** small changes in E — big changes in F
Impact of changing Clint or Q on high E drugs
Increase Clint:
- E already so high so doesn’t really change much but slight increase
———- bigger decrease in F
- Cl doesnt’ change
Increase Q (RL step of CL):
- increase Cl
- small decrease in E bc less time to extract
———- big increase in F
Changes in AUC with changes in Clint: high E drug
increase CLint — doesn’t change Cl
— F decreases though: Peak C decreases + AUC decreases
- no change in Cl, V, or t1/2***
Changes in AUC with increase in Q: high E drug
increase in Q: increases Cl
— slight decrease in E and increase in F
— increase in F and increase in Cl: cancel out so no change in AUC
Peak C: higher because F is higher
increase in Cl—- decrease t1/2 (steeper slope)
Impact of increase fu (decrease PPB): poor E
- lessen the restriction on elimination
increase fu: increase Cl;
increase in E; decrease in F ( minimal)
AUC decreases (bc Cl increases) + peak C decreases bc decrease in F
V and Cl increases: no change in t1/2
Impact of increase in fu (decrease PPB): high E drug
increase fu: doesn’t change Cl much
— little increase in E — big decrease in F
AUC: decreases (bc decrease in F)
Peak C (fxn of F and V): decreases bc decrease in F + increase in V
V increases + Cl doesn’t change —- so t1/2 increases
T or F: increase in fu causes a decrease in AUC total for both high + low E but no change in AUC free
T
Poor E: CL increases but not really F
—- AUC decreases but free doesn’t
High E: Cl doesn’t really change but F decreases
—- decrease in AUC but no change in free
*opposite
