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The following message was posted to: PharmPK
Hi to all,
firstly i would like to thank everyone discussing here, these threads
are enlightening to read, especially for beginners in
pharmakokinetics like me.
I am referring to the discussion "CYP450 interactions and hepatic
Trying to show the effects of a change in CLint (intrinsic clearance)
on Css yields the same ratio of change for low and high extraction
drugs, if you use the formulas of the well stirred model for CL and F
(where F=1-E) predictions and apply them to the example of Mr. Cawello.
The reason for this was given by Mr. Proost:
"From the basis equation during steady state, input = output, it
follows that the relationship between dosing rate and Css is
dependent on the ratio CL / F:
Dose / tau = CL / F * Css
This ratio CL /F is proportional to the intrinsic clearance (CLint),
and thus to the metabolic capacity, IRRESPECTIVE OF THE
HEPATIC EXTRACTION RATIO.
This can be checked easily from the numerical examples given by
Willi Cawello, or by combining the equation for the hepatic clearance,
liver blood flow and intrinsic clearance given by Mike Leibold (note
the fraction unbound should be added to the equation, but that
does not matter for the present discussion), and the equation
F = 1 - EH."
The factor CL/F can be rewritten using the terms of the well stirred
(Q*fub*CLint)/Q+fub*CLint / (1-(fub*CLint)/Q+fub*CLint)
which is indeed proportional with respect to changes in CLint.
The relative impact of changing Css will be the same for any
numerical value of CLint and therefore for low and high extraction
But what does that mean now? Am I wrong assuming that the greater
impact of changing CLint for low extraction drugs on Css can be
modeled using the well stirred model terms?
If that is the case, how can the changes in Css be described in a
Sorry for bothering you with that topic again, I hope it is not too
Thank you all in advance,
Clinical Pharmacy and Pharmacotherapy
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