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The following message was posted to: PharmPK
Dear all,
I have a theoretical question concerning a product which has a
significant
elimination in plasma. This compound undergoes hepatic and renal
elimination, but also plasma elimination (observed in vitro). The total
systemic clearance (CLsys) of this compound obtained after IV
administration
in rat is greater than the hepatic blood flow (CLsys > 100 mL/min/kg).
I've read on this forum that it can happen when a clearance is
present in
lungs, because the lungs in in series in relation to other organs :
in this
case, the total clearance is no more the sum of organ clearances. So
i can
imagine it can be the same thing when an elimination occurs in the blood
compartment.
So we think that Clsys is not the sum of each clearance (liver, renal
and
plasma), since all organs are not in parallel, but rather some sort of
product of the three clearances. Is there a known relation between
CLsys,
CLliver, CLrenal and CLplasma? Is it of the form : CLsys a*CLplasma*
(CLliver+CLrenal)?
Best regards
Cedric
[Simple, additive should work. Just because there are contributions
from more 'parts' of the body doesn't mean it has to be greater than
hepatic blood flow - db]
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The following message was posted to: PharmPK
Hi David,
Forget my remark on the CLsys >100, I should not have mentionned this
point.
The Rowland and Tozer's book states p.161, concerning the pulmonary
clearance, that this clearance is not additive to others, because of
"the
blood supply to the lungs being in series, rather than in parallel, with
other organs of elimination".
My feeling is that if an elimination pathway is present in plasma
(soluble
enzymes), the situation is similar and the total clearance is not the
sum of
the "plasma" clearance and other peripheral clearances (liver, kidneys).
Let's say my question is purely theoretical : with a compound which
undergoes elimination in plasma, are we in the same case the the
pulmonary
clearance mentionned in Rowland and Tozer's book?
If yes, how to deduce the "clearance caused by plasma enzymes" from
CLsys, CLliver and CLrenal?
If no, is the good formula really CLplasma = CLsys - CLliver -
CLrenal? and why isn't it the case with the pulmonary clearance?
Best regards
Cedric
[After review of page 161 cited above ;-) I still think clearance is
additive (despite the wording 'one exception to the additivity of
clearance is pulmonary clearance'). The comment on page 161 goes on
to refer to the calculation of clearance or more exactly the
concentration used to calculate clearance. It is referring to the
usual practice of measuring peripheral blood which represents blood
leaving the lung, not the concentration entering the lung as per
other tissue clearance calculations. If pulmonary clearance is
calculated correctly it should be possible to add it to other
clearances to achieve a total clearance. Blood clearance could be
treated the same way, except to use blood concentrations; arterial
and venous? Maybe a separate clearance in arterial and in venous
blood. A good PBPK model should help there? ;-) I wonder what that
does to kel = CL/V, oh well. - db]
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The following message was posted to: PharmPK
Hi Cedric,
I agree with David on the pulmonary clearance. PBPK simulations allow to
simulate this very well. This will depend on the importance of
pulmonary CL
values. But one can show that for clearance around the hepatic blood
flow
values, clearances are approximately additives and beyond there is a
slight
trend showing some derivation from strict additivity but not much.
Hope this helps ;-))
P.
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The following message was posted to: PharmPK
Cedric,
In the PBPK model in GastroPlus 5.0, any combination of tissues,
arterial
blood, and venous blood can incorporate either fixed CL (as CLint or
CL), or
saturable clearance via Michaelis-Menten kinetics using Vmax and Km
for each
individual enzyme in each tissue. The latter requires knowing the
expression
level of each enzyme in each clearing tissue as well as the Vmax and
Km for
the drug in question per unit of metabolizing enzyme.
Solution of the differential equations results in the superposition
of all
mechanisms without respect to their linearity or nonlinearity.
If you have sufficient data, fitting of any unknown parameters can be
accomplished as well.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
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The following message was posted to: PharmPK
Thanks for your answer David.
In fact, a PBPK model has been made ;) , and a plasma clearance has been
"optimized" to fit the data. I wanted to have an idea how to treat the
problem with a NCA approach, to compare PBPK with a more classical
technique. My real problem is that i don't manage to scale "a priori"
the in
vitro plasma clearance to obtain a correct fit of my data. My aim was to
have a "reference" value for this "missing clearance", knowing that
part of
this missing clearance is probably due to an elimination in the
plasma/blood. I didn't find in reference PK books i have a way to
treat the
elimination in blood.
Because blood 1) is in series to liver and kidneys, 2) is the
compartment
where observations are made, i had the feeling that the calculation
of this
missing clearance was not so straightforward. But it looks as if I
was wrong
(...again ^_^' ...)
Cedric
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The following message was posted to: PharmPK
Thanks for your answer David.
In fact, a PBPK model has been made ;) , and a plasma clearance has been
"optimized" to fit the data. I wanted to have an idea how to treat the
problem with a NCA approach, to compare PBPK with a more classical
technique. My real problem is that i don't manage to scale "a priori"
the in
vitro plasma clearance to obtain a correct fit of my data. My aim was to
have a "reference" value for this "missing clearance", knowing that
part of
this missing clearance is probably due to an elimination in the
plasma/blood. I didn't find in reference PK books i have a way to
treat the
elimination in blood.
Because blood 1) is in series to liver and kidneys, 2) is the
compartment
where observations are made, i had the feeling that the calculation
of this
missing clearance was not so straightforward. But it looks as if I
was wrong
(...again ^_^' ...)
Cedric
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