- On 25 May 2000 at 20:50:52, "Eric Masson" (emasson.at.anapharm.com) sent the message

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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 - On 29 May 2000 at 13:42:57, ml11439.at.goodnet.com (Michael J. Leibold) sent the message

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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 - On 30 May 2000 at 11:57:58, ml11439.at.goodnet.com sent the message

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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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