Back to the Top
Hi all,
Anybody happened to know some drugs / compounds with high biliary
clearance in rat? For example, biliary clearance is higher than 20 ml/
min/kg.
Thanks a lot!
Guoyu Pan
Back to the Top
Hi Pan
Though higher animals (humans) have a higher bile flow/day (350mL/
day), compared to rats (22.5 mL/day), the bile flow/day/kg body weight
is much higher in rats (112.5mL/day/kg; assuming a 0.2kg rat) when
compared to humans (5 mL/day/kg; assuming a 70 kg human).So, if a
compound has similar affinity to biliary excretion in rats and humans
(which some times may vary, depending on the compound) they have a
higher biliary excretion in rats compared to humans.
Comments welcome
Thanks
Pavan
Back to the Top
The following message was posted to: PharmPK
Dear Pavan,
Your statement about biliary clearance in rats and humans is
interesting but not necessarily correct. You seem to assume that
biliary clearance is proportional to bile flow, which is not
necessarily the case. Biliary clearance is a measure of the capacity
of the liver to excrete a compound into bile, whereas bile flow is the
amount of bile formed by the liver per unit of time.
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Email: j.h.proost.-at-.rug.nl
Back to the Top
The following message was posted to: PharmPK
I think everyone is forgetting about the fact that humans have a
gall bladder and rats don't. Thus bile flow measurement to the
intestine in
humans does not actually reflect human bile production because of
processing
that occurs in the gall bladder.
Dr. Daniel S. Sitar
Professor and Head, Dept. of Pharmacology and Therapeutics
Professor, Dept of Internal Medicine (Clinical Pharmacology)
Web Address: www.umanitoba.ca/medicine/pharmacology
Email: sitar.at.cc.umanitoba.ca
Back to the Top
I agree with Proost opinion. Because the help of active efflux
transporters, some compounds could have very high biliary clearance,
which could be greater than bile flow. For example, Taurocholate acid
biliary clearance is about 29.8ml/kg/min in rat, and DBSP biliary
clearance is 22.0 ml/kg/min in rat. I can attach related literature
if someone has interests.
I am doing some biliary excretion IVIVC study, it is interesting I did
not find a lot of compounds with high biliary clearance. That is why
I mentioned "biliary clearance higher than 20ml/min/kg in rat" in my
previous poster.
An interesting discussion came from Dr. Daniel. What is the influence
of gall bladder in biliary clearance measurement? Actually in human
it is not easy to collect bile samples directly, so how can we judge
compounds biliary excretion rate correctly?
Thanks!
Guoyu
Back to the Top
Dear Dr. Proost
I tend to disagree with your statement that"You seem to assume that
biliary clearance is proportional to bile flow, which is not
necessarily the case"
As Biliary clearance =Bile flow*Concentration in bile/concentration in
plasma
(Reference" Clinical Pharmacokinetics, concepts and applications,
Malcom Rowland and Thomas N Tozer)
So, in a way biliary clearance depends on the bile flow rate. If a
compound follows similar metabolic pathway in human and rats the
biliary clearance may be higher in rats. This is because biliary
clearance in this example happens to be ml/min/kg body weight.
Regards
Pavan
Back to the Top
Hello All,
If a compound is having significant biliary excretion in rats, it
doesn't mean that it will exhibit the same phenomenon in humans. The
molecular weight thershold for biliary elimination varies between
rodents and humans. It has been shown that the biliary excretion
increases substantially beyond 450 to 500 in humans, where as the same
threshold is much lower in rats (~ 200 to 250). So the molecular
weight of the compound in question also plays a pivotal role.
Its quite an interesting point raised by Daniel regarding the role of
gall bladder in biliary excretion.
Comments welcome
Ravi
Back to the Top
Dear Guoyu
In rat, drugs with molecular weight greater than 300 can be
excreted in the bile, whereas in human the molecular weight of greater
than 500 may be required for a drug to be excreted in the bile.
In addition to high molecular weights, drug excreted into bile
also required a strong polar group.
Eg. Many drugs which excreted in bile are glucoronide
conjugates which are more polar than the parent drugs.
So as per my opinion it will be better to select drugs whose molecular
weight is higher and additionally which under goes glucoronide
conjugation.
If you are interested to predict human clearance of biliary excreted
drug only from rat data, please try this equation...
1. Predicted human CL= Rat CL * human liver blood flow/rat liver blood
flow
OR
2. Human CL= Rat CL * (wt of human/ wt of rat) 0.75
But above approach (only from rat data) will produce large errors.
In this case, only CL/bile flow approach along with rule of exponents
is a reliable method for prediction of human clearance.
Another approach is normalization of clearance with a) bile flow/kg
liver wt or b) bile flow/ body weight.
I hope this may help you!!
Regards,
Prashant Nigade.
Back to the Top
The following message was posted to: PharmPK
Dear Pavan,
You wrote:
> As Biliary clearance =Bile flow*Concentration in bile/concentration
in
> plasma
> (Reference" Clinical Pharmacokinetics, concepts and applications,
> Malcom Rowland and Thomas N Tozer)
>
> So, in a way biliary clearance depends on the bile flow rate.
What do you mean with 'in a way'? This equation does not imply that
biliary
clearance depends on the bile flow rate. Indeed, bile flow rate may
affect
biliary clearance, but this is not necessarily so. In the above
equation,
changes in bile flow rate will affect primarily the concentration in
bile.
Biliary clearance is primarily dependent on the Vmax/Km ratio of the
transporters involved.
> If a
> compound follows similar metabolic pathway in human and rats the
> biliary clearance may be higher in rats. This is because biliary
> clearance in this example happens to be ml/min/kg body weight.
I don't understand your point. What has the metabolic pathway to do with
biliary clearance? And why is the unit relevant for the discussion?
I agree with the comments by Daniel Sitar, Guoyu and Ravi.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Email: j.h.proost.-at-.rug.nl
Back to the Top
The following message was posted to: PharmPK
Dear Prashant,
You wrote; "Many drugs which excreted in bile are glucuronide
conjugates which are more polar than the parent drugs. So as per my
opinion it will be better to select drugs whose molecular weight is
higher and additionally which under goes glucuronide conjugation."
The original poster was enquiring about compounds with high biliary
clearance. For the benefit of any non-specialist readers on this
list, we should be clear that biliary excretion of a glucuronide
conjugate is not biliary clearance. This is a metabolic process, and
as such is a manifestation of metabolic clearance, not biliary
clearance.
Regards,
Peter Rix
Kalypsys Pharmaceuticals, Inc.
San Diego, CA
Back to the Top
The following message was posted to: PharmPK
Ezetimibe (MW=409), sulindac (MW=356) and morphine (MW=285) all undergo
enterohepatic circulation in human. So it is not an absolute
requirement to
have high molecular weight.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-a-.simulations-plus.com
Back to the Top
Dear Peter,
I think Prashant wanted to tell us some glucuronide conjugates could
also be used as biomarker in biliary clearance study. For example,
some paper reported E2-17BG is excreted into bile... That is my
understanding. However, as I know, a lot of glucuronide conjugates
could be excreted into bile, but I did not find someone with high
biliary clearance. That is one of the reason I had poster here for
help.
With best regards,
Guoyu Pan
Novartis Institutes for BioMedical
Back to the Top
mebrofenin
Doxorubicin
methotrexate.
Look at this reference Drug Metabolism and Disposition Vol. 27, Issue
6, 637-644, June 1999
Kim Brouwer, Ken Brouwer and Ed LeClyuse's work with the B-clear
model have quite an extensive database of hepatobiliary excretion
compounds with correlates to in vivo studies.
Does that help?
Sanjeev Thohan
Director DMPK
Exelixis, Inc
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 "High biliary clearance compound" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)