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We have a small molecule drug when given iv to bile-duct cannulated
rats, over 20% of the dose was excreted unchanged in the bile.
However, when it was given po, less than 1% was recovered unchanged.
We do not have a radiolabeled drug, therefore, I have no information
on the amounts of metabolites formed.
I will appreciate help with interpreting the data. Was the
difference due to bioavailability? Or can there be other
physiological explaination.
Thanks,
Ellen
Ellen Cheung
Sr. Director, Preclinical Research
InterMune, Inc.
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The following message was posted to: PharmPK
Dear Ellen,
Enterohepatic circulation could account for the difference.
In the cannulated rat, once the drug is secreted in bile, it is
collected
without an opportunity for reabsorption. In a dose without
cannulation (iv
or po), the drug can recirculate extensively, being reabsorbed after
secretion back into the intestinal lumen. The drug could continue to
recirculate until it is cleared by metabolism, renal clearance, and/
or other
clearance pathways. It would be interesting to compare results from
an iv
dose without cannulation to what you obtained with. And more
interesting to
compare po doses in the same way.
Since your iv dose was cannulated, you might observe apparent
bioavailability > 100% for the po dose. At any rate, if there is
enterohepatic circulation, the bioavailability you observe will be
higher
than it would have been if all else is the same and the drug was not
reabsorbed.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
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
Hi,Ellen,
I think it is due to the intestinal extraction (luminal excretion and
intestinal metabolism) in po dosing. Actually, the greater metabolism
in po vs.
iv was observed for some drugs, such as morphine, acetominophen etc.
This
phenomenon is called "route dependent metabolism". That can be
explained by the
fact only part of the intestinal blood flow reaches the active region
of the
small intestine - enterocytes, but large fraction of blood flow goes
through
the non-active region - serosal layer. In addition, as an anterial
organ to the
liver, intestine plays an important role in first-pass removal and
thereby
reduce the availability of substrate reaching the liver, resulting in
less
biliary excretion in po administration.
Hope this will help.
Huadong
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The following message was posted to: PharmPK
Ellen,
After rereading your post, I think I misinterpreted it.
For some reason, I assumed that the po dose was not cannulated, and
that the
"recovered unchanged" 1% was in urine and/or feces. You didn't say
that, so
I should not have assumed it.
If the po dose was cannulated and only 1% was excreted unchanged in
bile,
then it appears that considerably less reached the systemic circulation.
That could be caused by a variety of factors, including: low
solubility in
the intestinal lumen, low permeability, and/or high first pass
extraction in
gut and/or liver.
How did the plasma concentration-time data differ between iv and po
doses?
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
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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Hi Ellen,
Thanks for your posting on biliary clearance.
Do you have an estimate of po bioavailability over 5%?
Low fraction absorbed (whether poor absorption, efflux pumping, or
gut metabolism) are all possibilities and probably most likely. But
I can think of another explanation - saturable metabolism. Often
following an iv bolus, there is a time when plasma concentration is
relatively high - perhaps much higher than from a po dose. If this
does not saturate the rate of uptake by hepatocytes, then there can
be a higher concentration (at least for a time) inside hepatocytes
following the iv dose. Then, if there is a saturable metabolic
pathway, canalicular pumping (which usually has a higher capacity
than oxidative metabolism) becomes a major route of clearance.
The distribution of cleared drug between metabolites and
transportation should be concentration dependent. Usually, we only
see the predominant route. Maybe if you give a larger po dose, you
will change the balance in favour of more biliary clearance.
Clearance/bioavailability will be dose (concentration) dependent by
all routes of administration.
Do you measure plasma concentrations at the same time? The ratio of
plasma to bile concentration can be quite informative. We have seen
bile to plasma concentration ratios over 1000:1 - that is a steep
gradient, and the hepatocytes just keep pumping and pumping!
Best regards.
Ted Parton
DMPK,
UCB (Celltech)
Slough, UK
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The following message was posted to: PharmPK
Hi Huadong,
"That can be explained by the fact only part of the intestinal blood
flow
reaches the active region of the small intestine - enterocytes, but
large
fraction of blood flow goes through the non-active region - serosal
layer."
Do you have an estimate of the fraction of intestinal blood flow
reaching
the active region of the small intestine?
Do you have good references on the subject?
I have another question :do you think that a drug (with good passive
absorption properties) coming from arterial blood and entering this
"active
region" can pass the basal membrane of enterocytes and be metabolized by
intestinal enzymes? i mean, do you think that a drug administered by IV
route could be significantly metabolized by intestinal enzymes?
Best Regards
Cedric
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