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The following message was posted to: PharmPK
Dear readers,
Does the presence of a small second hump towards the last time points
in a single oral dose concentration-time curve necessarily imply that
enterohepatic recirculation is present? How would one confirm that?
I was also wondering as to what could account for a small resurgence
of drug after its apparent disappearance at a late time point
following an iv-bolus dose?
Thank you for your suggestions.
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The following message was posted to: PharmPK
Hello
You can confirm this in normal vs bile duct cannulated rats. In case of
enterohepatic recirculation you should not see the secondary peak in
cannulated rats. Normal gastrointestinal transit times in various species
also can help you in this. It may also be possible that, depending on the
properties of your molecule, that a tissue might be acting as a depot
compartment. The release of the drug from the deep depot compartment may
also contribute to your findings. You can crosscheck this by first doing the
bile duct cannulated study.
Hope this helps
Atul
[An example Boomer .BAT file is at
http://www.boomer.org/manual/EG/ehrc0/ehrc.html - db]
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You don't say what the relative time frames are which is useful for
interpretation.
A peak occurring a few hours after the main peak may signify e/h
cycling especially if drug has largish molecular wt. But I would not
go overboard about this unless there was at least 3 or 4 data pts
giving a clear trend (upswing/peak/downswing), especially if no
previous evidence this occurs for your drug.
Alternatively, it may indicate dumping of part of the oral preparation
from the stomach into the upper duodenum (where most drugs are
absorbed). It would be great if you also had i.v. data which would
rule out this possibility, if the "shoulder " disappeared.
Of course if the assay was sensitive enough and you sampled
enough you may see 2nd or even 3rd "shoulders" progressively
decreasing in area which is even better.
You could canulate the common bile duct for extra support of e/h
cycling but this would be next to impossible in humans and hard
enough in animals expts.
Cheers,
BC
Bruce CHARLES
BPharm(Hons), GradDipBusAdmin, PhD, MPS
Associate Professor
Director, The Australian Centre for Paediatric Pharmacokinetics
University of Queensland, School of Pharmacy, QLD 4072
Australia
+61 7 336 53194 (TEL)
+61 7 336 51688 (FAX)
0403 022 252 (MOBILE)
b.charles.-at-.pharmacy.uq.edu.au
http://www.uq.edu.au/pharmacy/charles.html
http://www.mater.org.au/pharm/accp/index.htm
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The following message was posted to: PharmPK
Dear Khalili
Second peak in the plasma profile can be due to many causes.
Entrohepatic recirculation is one of them. In my experience, if the
Entro Reci was the reason, it usually occurs earlier (still depend on
the drug), what was the last point of blood sampling? Other reasons
could be associated with the absorption site, drug solubility at
different GI sites. If it was entro recir. bile collection should
give the answer. Can you please send me more information about the
compound and the sampling points.
Regards
Nabil B. Darwazeh
Wyeth-Ayerst Research
darwazn.at.war.wyeth.com
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There are other explanations for second humps in addition to
enterohepatic circulation. It can be difficult to determine which
cause(s) apply to a specific drug; however, we've found that
simulations can provide a great deal of insight if sufficient data
are available.
For example, in simulations for oral doses of drugs that exhibit a
second hump, we have found several possible explanations:
exsorption/secretion of drug from the gut wall (with
subsequent reabsorption) due to:
P-gp or other efflux protein effects
enterocyte concentrations higher than lumen
pH change from ileum to colon affecting
solubility/dissolution for ionized drugs
pH change from ileum to colon causing permeability change for
ionized drugs
A second hump due to exsorption and (re)absorption is more likely for
long half-life drugs with low protein binding. This results in
unbound blood concentrations becoming higher than the concentration
in the (gut wall) enterocytes, producing diffusion of drug from blood
to enterocytes, followed by diffusion from enterocytes to lumen.
Efflux transporters could add to this effect. This can happen for
both oral and IV dosage forms. Reabsorption of the exsorbed drug
could cause an increase at later time points.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
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.aaa.simulations-plus.com
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