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Hi, while reviewing papers using PBPK I found that eliminating
tissues e.g. liver there seems to be a conflict of opinion. For a
compound undergoing clearance from liver what would be appropriate
clearance term from the liver compartment in PBPK modeling
1) - (CL*Cliver/Kli)/V
2) - (CLint*fu*Cliver/Kli)/V
3) - (CL*Cliver)/V
4) - (CLint*fu*Cliver)/V
where CL is obtained after iv dosing as cl= dose/auc (assuming
monoexponential kinetics) and assuming that compound undergoes ONLY
hepatic metabolism
fu is fraction unbound in plasma
Kli is liver to plasma partition coeff
I am having some problem understanding as to why should clearance
occur from the concentration that comes out of the liver (Cliver/Kli)
rather than the one that is present in the liver (Cli). Is there any
consensus as to what should be used. Thanks.
Neil
Indranil Bhattacharya
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Neil:
For different modeling approaches and consensus on what has been used
in PBPK model, I would recommend a book by Reddy, M.B, Yang, R.S.H.,
Clewell, H.J., and Andersen, M.E. (2005): "Physiologically Based
Pharmacokinetic modeling Science and Application", Wiley and Sons,
Inc., Hoboken, NJ.
In PBPK models you can calculate hepatic (and otherwise) metabolism
explicitly, using Michaelis-Menten equation (so you may even not need
to use additional variables, like clearance). In any event, classical
PBPK models utilize PARTITIONING COEFFICIENT tissue:blood (Pt) as a
critical physicochemical parameter. Therefore, the rate of
metabolism in tissue, let's say in liver, which is related to
concentration of free chemical in this tissue, can be expressed
either in terms of concentration in venous blood equilibrated with
liver and returning from this tissue, or in terms of concentration in
liver divided by partition coefficient:
VolL*(dConcL/dt) = QL *(Cblood - (ConcL/PL)) - Vmax * ((ConcL/PL)/(Km
+(ConcL/PL)) )
Instead of Michaelis-Menten equation, some chemicals can be described
by first order metabolism and alternatively, using the same approach,
you can utilize clearance.
Hope it helps.
Best wishes.
Janusz Z. Byczkowski, Ph.D.,D.Sc.,D.A.B.T.
Consultant
212 N. Central Ave.
Fairborn, OH 45324-5006
voice (937)878-5531
e-mail januszb.-at-.AOL.com
homepage: http://members.aol.com/JanuszB/index.html
JZB Consulting web site: http://members.aol.com/JanuszB/consult.htm
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Dear Indranil,
You asked which of the folowing equations is appropriate to describe
hepatic clearance in a PBPK-model.
1) - (CL*Cliver/Kli)/V
2) - (CLint*fu*Cliver/Kli)/V
3) - (CL*Cliver)/V
4) - (CLint*fu*Cliver)/V
Equation 2 seems to be the most appropriate. Definitely the equations
using the plasma clearance directly (Nos. 1 ad 3) are of no use, at
least for compounds with high clearances. When putting the clearance
term into the liver compartment you have to use an intrinsic
clearance that is calculated regarding the liver blood flow rate
( CLint = CL*Qliv/(Qliv-CL) , where Qliv is the liver blood flow rate
and CL is the blood clearance). Then it depends on whether you want
to use an intrisic clearance that is related to the unbound fraction
of the drug. If yes, the intrinsic clearance given above has to be
divided by fu. Then you have to multiply this intrinsic clearance
with the unbound concentration in liver, which is the case in Eq. 2
- fu/Kli is nothing else than the unbound fracton in liver.
There are also other possibilities to set up the equation, but the
logic is always the same. The way to calculate the intrinsic
clearance and the equation used must fit together, such that the
combination leads back to the plasma or blood clearance.
You can find more information about calculating clearances in PBPK-
models in chapter 16 of the manual of the PBPK-software PK-Sim which
can be downloaded here: http://www.bayertechnology.com/eng/download/
PK-Sim_SoftwareManual.pdf
Freundliche Gruesse / Best Regards
Walter Schmitt
--
Bayer CropScience Aktiengesellschaft
BCS AG-D-MEF
Monheim, 6550
E-mail: walter.schmitt.-a-.bayertechnology.com
Web: http://www.bayercropscience.com
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