Back to the Top
The following message was posted to: PharmPK
dear all,
i had an question regarding the clearance of a molecule.,once
administered by i.v the compound concentrations in plasma and bile
were measured.results indicate that the concentrations acheived in
bile are more than 3 fold to the plasma counterpart.but when we see
the % dose, the % dose excreted in bile was very less compared to
plasma.
We also did a excretion study in faeces, urine but surprisingly we
could not see any concentrations in faeces and very less in urine. So
my question is what actually playing in b/w the excretion of drug from
bile to faeces since it is generally said that the compound in bile is
excreted into faeces.
i would rule out the involvmment of any enterohepatic recirculation
for we did not observe an second peak pheanomenon and no
glucuronidation and thus glucuronide hydrolysis is said to be
happening as the molecule is not undergoing any phase II metabolism.
please clarify me in such regards.
--
k.v.bhargava
Back to the Top
The following message was posted to: PharmPK
I wouldn't rule out EHR yet. Lack of a second peak does not mean EHR is not happening - it could simply mean that the amount released from the gallbladder is not not large enough to produce a second peak (if EHR is indeed happening). In those cases, you would simply perceive the drug as having an "extended half-life" (how long is the half-life of your compound?). And what species was used in your excretion study? Rats don't have gallbladders so even in the presence of large EHR you wouldn't see a second peak. Lack of glucuronidation also doesn't exclude the possibility of EHR, in my opinion. Does your compound have good oral bioavailabiltiy? If so, all that is excreted in the bile could be reabsorbed, which is why you are not finding it in the feces. Finally, there is a chance your compound is simply degrading either in the feces samples or during it's transit through the intestine once it comes out in the bile. Was you excretion study done with a radiolabeled compound? If so, a complete lack of
Back to the Top
The following message was posted to: PharmPK
Dear Vijaya
I also would not rule out EHR of either parent or a metabolite.
As Edgar Schuck stated in his reply absence of a second distinct peak does not mean an absence of EHR.
Simulations carried out using the mechanistic EHR model built into the ADAM absorption model of Simcyp suggest that the physiological and metabolic circumstances under which distinct peaks attributable solely to EHR are obtained are probably quite unusual. Significant accumulation of drug/metabolite in the gall bladder (of species having such) is required together with a very rapid release of a large proportion of the GB contents. Sufficiently high accumulation in the GB is limited where regular release of its contents is triggered either by the cycle times of the fasted state interdigestive migrating motor complex (IMMC) or by food intake (or even the thought of food). Also there is little evidence of rapid release rates from the GB (akin to a bolus release) rather there seems to be a gradual gentle pulsed release ... of course, as in general with Modelling & Simulation, such simulations do not rule out EHR as the major mechanism underlying a particular double peak phenomenon but they can provi
Back to the Top
The following message was posted to: PharmPK
thanks for the message. we had used wistar rats for the study in urine
and faeces. the compound had a good bioavailability of 85% and the
half life is around 2 hours. but the clearance was 63ml/minkg. can u
tell me what might had happened? if there is no second peak but the
involvement of enterohepatic recirculation, how to check in rats. any
reference for that?
please help me.
[To explore ehrc you might consider cannulating the rat bile duct - db]
Back to the Top
The following message was posted to: PharmPK
Dear k.v.,
The important physiological parameter for estimating the contribution to
total clearance from biliary clearance is the bile flow rate. In rat, I
estimate this to be about 0.75mL/hour (but don't quote me on that),
which is around 3mL/hour/kg or 0.05mL/min/kg. Multiply this by 3, your
bile-to-plasma ratio, and your biliary clearance is 0.15mL/min/kg, which
is 0.25% of the total clearance. It would be most surprising if you
could see any enterohepatic recirculation on this level! Likewise, you
will struggle to find parent compound in faeces at 0.25% of the dose. As
a general target, I would not worry about biliary clearance (in terms of
high clearance in rat) until the bile-to-plasma ratio reaches about
100:1 (CL=3mL/min/kg). However, it means other things apart from
clearance, but that is another subject.
You have not said if there were any metabolites in the bile. In broad
terms, biliary clearance follows polarity, and so the export of oxidised
or glucuronidated metabolites in bile will be much faster. As you have
some parent in bile, I expect you have a lot more drug in bile in the
form of metabolites. You may not be able to quantify them without
standards, but you can make an estimate.
Ted Parton
Director, RDMPK, UCB, Slough
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Clearance mechanism in bile" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)