Metabolite PK Flashcards
Parent drug fate
-in/active metabolite
-excreted in urine as parent drug
Contribution of metabolites to drug response
-can affect PK of drugs and alter response
Metabolite mechs
-inhibit CYP
-bind to plasma proteins
-have pharmacological activity
-toxicity
Prodrugs
-drug with no pharma activity that is converted to an active metabolite in vivo
Rate-limiting step
-most effects of metabolites are concentration-dependent
-need to understand formation and elimiation kinetics of metabolism
-slowest step
-defines PK profile
Formation and elimination kinetics
drug A –(kf)–> metaboliteAm –(km)–> elimination
dAm/dt = kfA - KMAM
formation-elimation
parent drug and metabolite concentration on graph when formation is slow and elimination is fast
-parallel-ish lines
-dec with each other
parent drug and metabolite concentration on graph when formation is fast and elimination is slow
-parent drug steep dec
-intersects high metabolite curve
info on metabolite kinetics
come from parent drug
low k value
slow
high k value
fast
apparent half life of parent drug
use kf
-same as true half life
true half life of parent drug
use kf
-same as apparent
apparent half life of metabolite
use smaller k
true half life of metabolite
use km
formation rate-limited drug things
-true t1/2 of metabolite is SHORTER than t1/2 of parent drug
-apparent t1/2 of metabolite SIMILAR to t1/2 parent
-kf«km
-typical of most drugs
elimination rate-limted drug things
-apparent and true t1/2 is LONGER than t1/2 parent
-kf»km
-typical of prodrugs
-graph intersects
CYP inducer effect on parent drug and metabolite half life in formation rate-limited
-decreases both
-think parallel lines
Css in formation rate-limited
-determined by t1/2
-same for metabolite and parent drug
Css in elimination rate-limited
-determined by t1/2
-LONGeR for metabolite than parent drug bc longer t1/2
Metabolite PK after ORAL dosing
-might have high first pass effect
-high metabolite to parent ratio compared to IV
When ORAL drugs have high EH and metabolite is INactive
-concentration of parent correspond to effect
-IV leads to quicker response
-low F of drug requires higher dose
When ORAL PROdrug with high EH
-shorter onset
-more intense response after oral than IV
-low F of PROdrug does not mean poor therapuetic effect