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Hi
My name is Andrea Diniz and I'm initiating in PK studies.
I'm studing pk of a flavonoid after extract plant administration. And
the flavonoid presented enterohepatic reabsorption. So, how can I
calculate flavonoid half-life elimination if, really, it has two?
And about the absorption parameters? How can I calculate the
absorption constant? What I need evaluation? Two absorptions
constants? Two eliminations constant?
Thanks for help and sorry for my bad English.
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Dear Andrea,
Modeling enterohepatic circulation (EHC) presents an interesting set of
challenges. In species with a gall bladder, there are two parts to
EHC, one
is continuous and one is triggered at mealtime. In human, about 25% of
the
biliary flow is continuously recirculated, with the remaining 75%
stored in
the gall bladder. At mealtime, the gall bladder empties so the flow is
maximum. In rat (no gall bladder) all of the recirculation is
continuous.
One effect of EHC can be that (because drug molecules are absorbed
more than
once) the apparent fraction absorbed can actually exceed 100%.
As far as an absorption rate "constant", please recognize that there
is no
such thing. There is an absorption rate _coefficient_ that is
time-dependent. Although assuming a constant Ka value can sometimes
provide
an adequate model, it can also be very misleading. State-of-the-art
simulation packages such as GastroPlus(tm) use mechanistic models
based on a
large number of differential equations that account for the many
phenomena
that are involved in oral absorption and EHC. These include local
variations
in solubility and permeability, as well as complexities like gut wall
metabolism and EHC.
Good luck with your study - and don't worry about your English. It's
just
fine.
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.at.simulations-plus.com
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Hi
If the compound is reabsorbed then this is a distribution process and
so I can't see how this would make apparent fraction absorbed greater
than one? In my understanding only clearance, non-reversible removal,
of the compound will contribute to the AUC and so the apparent
bioavailability. If you have any references on this matter I'd be very
interested.
Cheers
James
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The following message was posted to: PharmPK
Consider a drug that is 100% absorbed, with little or no enterohepatic
circulation because no food was given to trigger gall bladder emptying
during the sampling times. You would observe a certain AUC. Remember
that Fa
= 100%.
Now administer the drug again, but with food given at certain times
during
the sampling. The secondary peaks would cause an increase in AUC. So
there
is an _apparent_ Fa>100%. The same molecules are being absorbed more
than
once.
We see this effect when fitting simulation models to drugs like
sulindac,
ezetimibe, and morphine.
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.-at-.simulations-plus.com
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The following message was posted to: PharmPK
As a footnote to the discussions on enterohepatic recycling, it can be
useful to calculate the "effective half-life" to characterise drug
accumulation:
Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J
Clin. Pharmacol.. 1995; 35: 763-766
Regards,
Charlie
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