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The following message was posted to: PharmPK
Dear all,
We are working with a compound which is highly water soluble. We
have done 2 doses of pk studies in both oral and IV route. The
Bioavailability obtained is around 85-90%, half life in both the
routes was same (apprx 1h), since BA is good the Volume of
distribution and Clearance were identical in both the routes. The
compound had rapid absorption (tmax was the first time
point=10min, oral).
We have observed a very strange plasma profile of this compound.
In oral dose study it showed one compartment behaviour, first
point is the tmax and linear decrease in the conc. We have around
8 to 10 points, all the points lie on the same line (its like a
calibration curve). Where as in IV study we are seeing two
compartment behaviour, where there is clear distribution phase
(around 4 points) and then gets eliminated (4-5 points)
What may be the reason for this kind of behaviour?
I feel it is very strange to see one compartment behaviour with
oral route and two compartment behaviour with IV route? (oral: Why
after absorption into the central compartment, i.e., blood not
undergoing distribution and getting eliminated, whereas in IV
route where the compound is injected directly into the blood
undergoes distribution and then getting eliminated)
Any comments, explanations for this?
Thanks in advance for your input.
Regards,
B.L.Suresh
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The following message was posted to: PharmPK
Suresh,
I think we may need further information. For instance I would like to
know
if plasma concentration ranges were comparable by both IV and PO routes.
If YES this is definitely very strange !?! There is no relevant
explanation
except if your analytical method is not discrimant enough. In this case
we
should consider that the PO given drug is modified (during the
absorption
process)to give an entity that is not distributed but dosed by your
system
as the initial drug. Is there any risk that your analytical method
could be
like this ?
If NOT I assume that "PO" plasma concentrations are much lower than IV
ones.
In this case we should consider the fact that there is some saturation
process interfering in your measurements when the drug is given IV.
fraction bound <--> free fraction <--> "distributed" fraction
Saturation of the "bound/free" equilibrium leads to enhancement of the
ratio
"distributed/free" per IV.
These are only hypotheses I thought of. Does it make sense ?
Regards,
Frederic
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The following message was posted to: PharmPK
Dear Suresh,
What you have observed is indeed strange. I think we need some more
information in order to explain it. For example:
a)did you administer the same formulation and dose orally and iv?
b)what is the chemical nature of the compound? are its properties
affected
by pH?
c)is the compound metabolized in the body by a saturable, concentration-
depended process?
Regards
K. Avgoustakis, PhD
University of Patras,
Greece
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Dear Sures
> We have observed a very strange plasma profile of this compound.
> In oral dose study it showed one compartment behaviour, first
> point is the tmax and linear decrease in the conc. We have around
> 8 to 10 points, all the points lie on the same line (its like a
> calibration curve). Where as in IV study we are seeing two
> compartment behaviour, where there is clear distribution phase
> (around 4 points) and then gets eliminated (4-5 points)
I would not say this is strange……I would say it is
quite common.
> (oral: Why after absorption into the central compartment, i.e., blood
> not
> undergoing distribution and getting eliminated, whereas in IV
> route where the compound is injected directly into the blood
> undergoes distribution and then getting eliminated)
let’s clarify first your terminology. After IV
injection (in a two comp.model), distribution and
elimination are simultaneous processes
:distribution+elimination=Disposition (the drug does
not distributed and after eliminated…) so you have Two
DISPOSITION phases, governed by alpha and beta
constants………In a two compartment drug the terminal
slope represents the slow disposition phase and the
constant of this slope is beta.
After oral administartion, absorption, distribution
and elimination are again simultaneous processes but
if absorption (even if rapid) is slower than the fast
disposition phase you probably will obtain an oral
curve looking like a one compartment drug.
Let’s see it from a mathematical point of view. In the
attached excel file you have the equation (for oral CP
versus time) and some simulated curves.
[Available on request from bibilina.aaa.yahoo.com - db]
The blue one is
the IV.
When ka value is very similar to k21 the third
exponential have a negligible value, so the cp-profile
"collapse" to a bi-exponential one.
And look at the sequence between alpha, ka and beta
Alpha>ka>beta
The IV blue curve is a nice classical two compartment
curve while the pink oral one (same drug same
parameters) seems a one compartment drug.
Hope this helps
Marival
Marival Bermejo
Prof. Titular Farmacia y Tecnología Farmacéutica
Facultad Farmacia. Universidad de Valencia
España.
http://www.uv.es/~mbermejo/absorption.html
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