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The following message was posted to: PharmPK
I have a question for enterohepatic recirculation of a drug:
The rat has no gall bladder, does this mean the multiple peaks of a
compound observed in rat plasma are surely not due to enterohepatic
recirculation? If a drug undergoes enterohepatic recirculation, how
does the plasma concentration-time curve look like?
Thanks!
Ru Yan
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Dear Ru Yan,
Just a quick note. Rats don't have gall bladder, but they have bile
duct. As I have also observed in my experiments in which the bile
duct is cannulated, significant amount of bile is excreted into the
duodenum. Thus, enterohepatic circulation is valid for rats.
Yusuf Cem Kaplan,MD
Dokuz Eylul University
Medical Faculty
Department of Pharmacology
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The following message was posted to: PharmPK
Dear Ru Yan and Yusuf,
Yes, rats can have enterohepatic circulation even though they do not
have a
gall bladder, so the enterohepatic circulation is continuous (so
secondary
peaks due to EHC seem unlikely).
For species with a gall bladder, part of the enterohepatic
circulation will
be continuous (typically about 25%) but most will accumulate in the gall
bladder during fasted state, and then will be released at mealtime
over some
period of time (we use 30 minutes for gall bladder emptying as the
default
time in GastroPlus). Such release often results in a significant
secondary
peak, and even the apparent effect of bioavailability > 100% (because
some
of the drug can be absorbed more than once).
We often see data from "fasted" studies with samples taken for 24
hours or
more after the dose. I always ask if the subjects were starved for 24
hours
(pause for laughter) and then ask when meals were given. Mealtimes
can often
explain "unusual" behavior on plasma concentration-time data.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.aaa.simulations-plus.com
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Agreed with Walt. Depending on the phys chem props of your compound,
dosage, %F , and sampling times after oral dosage you may see a small
shoulder than can increase with dose. The formation of a distinct
second peak will not be observed in rats. To effectively see this
phenomena, you may have to sample at 30-45 min intervals after the
Tmax of the compound. Alternately you can obtain Bile Duct
Cannulated rats (BDC rats) from commercial vendors and determine the
plasma profile in intact animals, as well as the plasma and bile
profile from the BDC rats. This makes for a very nice study from
which you can derive much more information than a plasma study.
Sanjeev Thohan, PhD
Director, DMPK
Exelixis, Inc
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