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The following message was posted to: PharmPK
Dear everyone,
I need somebody to help me make the brain clear now. One
water-soluble compound (glycoside) was reported to have a low
intestinal permeability. This feature resulted in a extremely low
bioavailability after it was orally dosed. Meanwhile, this compound
was also reported to be absorbed rapidly (Tmax was less than 10 min).
So, I am confusing, since this compound is difficult to pass through
the intestinal membrane, how can it be absorbed so fast then? Is
there any explanation for this fact?
Thanks in advance.
Juxiu He
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Dear Juxiu:
Tmax is a function of kel and ka. For a given ka value, Tmax decreased as
ke increased.
It is possible if your drug has a very short elimination half-life.
Best regards,
Sam Liao, Ph.D.
PharMax Research
270 Kerry Lane,
Blue Bell, PA 19422
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Dear everyone,
Thanks for your input in the talking about the intestinal
permeability and Tmax. I still have some question. One water-soluble
drug showed low intestinal permeability, but short Tmax (about 20min)
and high absorption rate constant (Ka = 1.5 /h), that is, high speed
of absorption. How to explain this low intestinal permeability but
high Ka? Are there some other factors except the
permeability influencing the Ka? If there are, what are them?
Any kind of comment is highly appreciated.
Juxiu
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The following message was posted to: PharmPK At 07:54 PM 9/1/02, He
Ju Xiu wrote:
>Thanks for your input in the talking about the intestinal
>permeability and Tmax. I still have some question. One water-soluble
>drug showed low intestinal permeability, but short Tmax (about
>20min) and high absorption rate constant (Ka = 1.5 /h), that is,
>high speed of absorption. How to explain this low intestinal
>permeability but high Ka? Are there some other factors except the
>permeability influencing the Ka? If there are, what are them?
>
How did the drug "show low intestinal permeability"?
If permeability was measured in Caco-2, MDCK, Ussing chamber, or
artificial membrane, then you might observe a low permeability in
vitro, when the actual in vivo permeability could be quite high. You
did not say what in what species Tmax was taken - human, dog, rat?
What was the experiment and what were the conditions (concentration,
pH on each side of the membrane, etc.)? Is the drug likely to be a
substrate for a carrier-mediated transporter? If you run an
experiment for a drug that is transported by PepT1 with an apical pH
of 7.4, you will see little transport. But reduce the pH to 6.5 and
it will transport very well.
If the drug is in solution and stays in solution, then permeability
alone controls the rate of absorption. Permeability can encompass
three routes - passive absorption, paracellular transport, and
carrier-mediated transport. Perhaps the morphology of the cells in
your in vitro experiment is significant different from that of the
duodenum and jejunum in vivo, so that one or more of these mechanisms
is different.
Two years ago at the San Francisco Millenial Congress, Dr. Phil
Burton of Pharmacia in Kalamozoo, Michigan, reported on a compound
that showed similar behavior in rat. He had measured permeabilities
in rat jejunum, ileum, and colon, yet when he used these values in
GastroPlus to predict the absorption rate and plasma
concentration-time, he did not show the rapid absorption and short
Tmax that he observed. So he went back to the lab and measured the
permeability in duodenum and discovered that it was something like 20
times higher than jejunum! With that value, he was able to match his
results. Was it a transporter? I don't recall, but it seems likely.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
E-mail: walt.aaa.simulations-plus.com
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The following message was posted to: PharmPK
Dear Dr. Woltosz,
Thanks quite a lot for your helpful discussions. Actually, the
"low intestinal permeability" of my compound was reported in two
literatures. One measured the permeability using in situ
recirculating perfusion technique (with recirculating solution at pH
6.5, containing 0.34mg/ml of the compound), and the other using
in-vitro everted sac method on jejunum. Both of them studied in rats.
Based on those studies, can I say that the compound has "low
intestinal permeability"?
The high Ka and short Tmax I talked about were obtained from
orally dosed rats. In some other literatures, even more shorter Tmax
(5-15 min) was reported. If the "low intestinal permeability" really
exists with my compound, can I say that it is some other factors such
as transporter but not permeability that is controlling the rate of
absorption?
Thanks in advance.
Juxiu
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