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The following message was posted to: PharmPK
Hi all,
In the recirculation-mode perfused liver preparation, it is my
understanding that biliary clearance is calculated (in the same way as
renal clearance in vivo) as:
CL(bile) = Mass(bile)/AUC(0-inf)
Where Mass(bile) = the total mass of material recovered in bile (over
infinite time) and where AUC(0-inf) = the AUC under the perfusate
concentration vs. time profile.
I have a feeling that the same equation cannot be applied in the
single-pass liver perfusion (conducted in a loading-washout design) .....
Am I correct in this?
If I am correct, can anyone advise what is the appropriate equation for
determining biliary clearance (CLbile), particularly in the case when
steady-state (with regards to outflow perfusate/bile concentrations) is
not achieved before the washout phase is commenced?
Finally, can anyone point me in the direction of a good description of the
mathematical treatment of various perfusion designs?
Thanks in advance!
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The following message was posted to: PharmPK
Dear Andrew,
You wrote:
> biliary clearance is calculated as: CL(bile) = Mass(bile)/AUC(0-inf)
> I have a feeling that the same equation cannot be applied in the
single-pass liver perfusion Am I correct in this?
Defining biliary clearance as the rate of biliary excretion divided by the
perfusate concentration, this equation can be used. The way of drug
administration, in this case recirculatory or single pass, does not make a
difference.
Please note that for high-extraction drugs the 'perfusate concentration'
may refer to the concentration entering the liver or leaving the liver, or
some average concentration; this makes a large difference! Usually,
assuming the well-stirred model, the outlet concentration is used.
Best regards,
Hans Proost
Dept. of Pharmacokinetics and Drug Delivery
University of Groningen, The Netherlands
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The following message was posted to: PharmPK
Referring back to the original posting by Andrew Powell, and the recent
one by Hans Proost on this subject...is everyone talking about an in vitro
model with an excised liver, or is this an anesthetized animal model? I
am curious about whether these equations would also apply to an in vivo
model in a conscious, freely-moving animal? Would collection and analysis
of portal blood (to provide the AUC of the test article) and simultaneous
collection of bile (to provide the Mass(bile)portion) be applicable to
this equation? Should we be providing a continuous infusion of test
article (e.g. continuous gastric or duodenal infusion) to establish
something analogous to a steady-state in the portal blood? Under such
conditions, I wouldn't be surprised if CL increased dramatically vs. an
anesthetized model, or an in vitro model. Like Andrew, I'm seeking the
best way to represent it.
Thanks for your opinions!
Candice Kissinger
BASi
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The following message was posted to: PharmPK
Dear Candice,
The equation applies equally well to the in vivo situation, and is not
restricted to steady-state conditions. The choice of the sampling site is
critical, as I explained in my earlier message. In the case of in vivo
animal studies, the logical choice is to use 'normal' plasma concentrations
for the calculation of AUC. The calculated biliary clearance (Total amount
excreted into bile divided by AUC) is then interpreted as the amount of
plasma cleared from the drug via the bile per unit of time (and thus a
certain fraction of the total clearance). It does not necessarily reflect
the capacity of the liver to clear drugs via the biliary route; in case of a
high hepatic extraction, the 'effective' concentration 'driving' the biliary
excretion is lower than the central plasma concentration. So the appropriate
site of measurement depends on what you want to know.
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.aaa.rug.nl
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