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Dear colleagues,
Is it possible to measure partial metabolic clearance from steady-state data
without having to use radiolabelled compound? For example, would the
principle of juxtaposition for AUC (AUC0-tau MD/AUC0-inf SD) apply also for
partial metabolic clearance (i.e., Ae met0-tau /AUC0-tau parent MD/ Ae met
0-x/AUC0-x Parent SD)?
Thanks,
Eric Masson, Pharm.D.
Scientific Director,
Anapharm inc
2050, boul Rene-Levesque West,
Ste-Foy, QC, Canada, G1V-2K8
418-527-4000 (EXT:222)
FAX: 418-527-3456
emasson.aaa.anapharm.com
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Eric,
There are a few derivations in Gibaldi& Perrier regarding fraction
metabolized, metabolite and parent drug clearance. The derivations occur
from the relationship:
KfVpCpss= KmVmCmss
Where at steady state, the rate of formation of the metabolite(KfVpCpss)
is equal to the rate or its removal (KmVmCmss). Since, the rate of formation
of the metabolite is equal to fraction of the parent drug cleared by metabolism
times the overall systemic clearance, the following relationship occurs:
FmClpCpss= ClmCmss
Fm= fraction metabolized
Clp= clearance of parent drug
Cpss= steady state concentration of parent drug
Clm= clearance of metabolite
Cmss= steady state concentration of metabolite
Kf= constant of metabolite formation= FmK
FmClp= FmKVp= KfVp
Rearranging for Clm:
Clm= FmClpCpss/Cmss
From this equation, the partial metabolic clearance could be calculated
from the steady state concentrations of the parent drug (Cpss) and the
metabolite (Cmss) with knowledge of the systemic clearance of the parent
drug (Clp) and the fraction metabolized (Fm).
Fm or fraction metabolized can be estimated from the following equation:
Fm= [AUCm]p/Dp x Dm/[AUCm]m
Where the faction metabolized (Fm) is equal to the ratio of the AUC for
the metabolite after administration of a dose Dp of parent drug to the AUC
for for the metabolite after administration of an "equimolar" dose of
metabolite (Dm).
[AUCm]p= AUC of metabolite after Dp of parent drug
[AUCm]m = AUC of metabolite after Dm of metabolite
This would require some assay specificity for the metabolite, as in
the case of NAPA, to circumvent the need for radioactive labeling.
I hope this was of some help!
Mike Leibold, PharmD, RPh
ML11439.aaa.goodnet.com
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Eric,
There are a few derivations in Gibaldi& Perrier regarding fraction
metabolized, metabolite and parent drug clearance. The derivations occur
from the relationship:
KfVpCpss= KmVmCmss
Where at steady state, the rate of formation of the metabolite(KfVpCpss)
is equal to the rate of its removal (KmVmCmss). Since, the rate of formation
of the metabolite is equal to fraction of the parent drug cleared by metabolism
times the overall systemic clearance(partial metabolic clearance)times the
plasma
concentration, the following relationship occurs:
FmClpCpss= ClmCmss
Fm= fraction metabolized
Clp= clearance of parent drug
Cpss= steady state concentration of parent drug
Clm= clearance of metabolite
Cmss= steady state concentration of metabolite
Kf= constant of metabolite formation= FmK
FmClp= FmKVp= KfVp
Rearranging for Clm:
Clm= FmClpCpss/Cmss
From this equation, the "clearance of the metabolite" could be calculated
from the steady state concentrations of the parent drug (Cpss) and the
metabolite (Cmss) with knowledge of the systemic clearance of the parent
drug (Clp) and the fraction metabolized (Fm).
Fm or fraction metabolized can be estimated from the following equation:
Fm= [AUCm]p/Dp x Dm/[AUCm]m
Where the faction metabolized (Fm) is equal to the ratio of the AUC for
the metabolite after administration of a dose Dp of parent drug to the AUC
for for the metabolite after administration of an "equimolar" dose of
metabolite (Dm).
[AUCm]p= AUC of metabolite after Dp of parent drug
[AUCm]m = AUC of metabolite after Dm of metabolite
The product of FmClp would be equal to the partial metabolic clearance,
while Clm would be equal to the "clearance of the metabolite".
However, this would all require some assay specificity for the metabolite,
as in the case of NAPA, to circumvent the need for radioactive labeling.
I hope this was of some help!
Mike Leibold, PharmD, RPh
ML11439.at.goodnet.com
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)