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Can anyone help me with an equation/s to calculate metabolite clearance =
after oral administration of parent drug at steady-state
=20
regards
=20
brian=
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Brian,
Clearance of the metabolite cannot be estimated without knowing 2 things =
in addition to the concentration time course of the metabolite. The =
first is the oral bioavailability (F) of the parent from the dose =
(DoseP). The second is the fractional conversion of the parent to =
metabolite (F2M).=20
[The following relationships refer to the duration of the dosing =
interval at steady state]
AMTP=3DF*DoseP ; amount of parent that is eliminated
AMTM=3DF2M*AMTP ; amount of parent that is converted to metabolite
CLM =3D AMTM/AUCM ; clearance of metabolite using AUCM (AUC of =
metabolite)
If you know the oral bioavailability (F) then you only have to assume a =
value for F2M.=20
F2M can only really be known by administering the metabolite and =
calculating CLM then re-arranging the equations above to solve for F2M. =
There are other ways that rely on making other assumptions e.g. =
collecting metabolite in urine and assuming all the metabolite is =
excreted in the urine.
Nick
--=20
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand=
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The following message was posted to: PharmPK
There is a nice chapter (21, Metabolite Kinetics) on this in Rowland &
Tozer's "Clinical Pharmacokinetics" (3rd ed. 1995)
For multiple dosing at SS;
Average Conc of metabolite at steady-state = (Fm x F x Dose)/(Dosing
interval x Metabolite clearance)
However, the absolute clearance of metabolite cannot be calculated
unless you know (or assume) values for Fm, which is the fraction of Dose
of parent drug which is converted to metabolite, and F which is the oral
bioavailability of the parent drug.
Cheers
Bruce CHARLES DSc, PhD, BPharm (Hons), GradDipBA
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Hi Brian
=20
As an alternative you can use physiologically based "bottom-up" =
modelling to calculate clearance as well as the concentration-time =
profiles for both parent and metabolite. Of course you need some =
physicochemical (can be predicted from its structure) and in vitro data. =
For more detail please see:
Rowland Yeo K, Jamei M, Yang J, Tucker GT and Rostami-Hodjegan A (2010) =
Physiologically-based mechanistic modelling to predict complex drug-drug =
interactions involving simultaneous competitive and time-dependent =
enzyme inhibition by parent compound and its metabolite in both liver =
and gut-the effect of diltiazem on the time-course of exposure to =
triazolam. European Journal of Pharmaceutical Sciences 39:298-309
http://dx.doi.org/10.1016/j.ejps.2009.12.002
=20
Regards
Masoud =20
Senior Scientific Advisor and Head of M&S, Simcyp Limited
Honorary Lecturer, School of Medicine, The University of Sheffield, UK=
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Dear All,
I am in a similar situation with regards to metabolite modeling. I have plasma and metabolite measurements. Metabolite was measured in PMBCs. I understand the identifiability issues around metabolite volume and fraction for conversion. I have some reasonable estimate of bioavailability of the parent molecule. I do not have any estimate on the fm (fraction parent to metabolite conversion). I read through some of the suggestions like fixing the metabolite compartment same as parent etc but clearly it is not valid assumption as we know the PMBC volume is not same as parent volume of distribution. I know renal clearance is a major route of elimination of the drug so I have to have two eliminiations in the model, Cl through metabolism and Clother. I appreciate any suggestions on modeling parent and metabolite data simultaneously.
Regards,
Ayyappa Chaturvedula
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