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One of our drugs gets converted following oral administration to a
metabolite. Following its oral administration we observe an increase
in T-max, C-max and AUC without any change in T-half of the metabolite,
compared to the parent drug, in rat plasma. Following iv
administration of the same drug, we observe a decrease in the AUC and
T-half of the same metabolite, compared to the parent drug. I will
appreciate if PharmPK members can enlighten me on what could be going
on and we may interpret the results.
Thanks
Ananda
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Ananda,
Question: Is the T-half of the parent drug the same for oral and IV
dosing?
Art Straughn
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When given po the T-half for the parent drug and its metabolite is
around 6 hrs. When given iv the T-half of the parent drug is 20 min
and its metabolite is 40 min.
Thanks
Ananda
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You did not specify how many drugs you do have under study. If you have
more than one drug under study then automatically that is drug
interaction cause there is a drastic statistical change in the
Pharmacokinetic parameters.
However if you do have only one drug under study then probably it is
binding to the proteins.From: Ananda Sen
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Hi Art,
Yes, the half life of a particular drug remains same for oral as well
as iv administration except if the drug is in controlled or extended
release dosageform.
regards
sanjay
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Ananda,
Without further information related to the experiment it is difficult to
tell exactly what is going on here, but one could speculate the
following:
The model for your parent drug is a two compartment and when it is given
orally the absorption is much slower than either distribution or
elimination
and the terminal T-half is reflective of absorption and not elimination
(i.e. "flip-flop" model). In similar fashion, unless the metabolite is
eliminated more slowly than the parent drug, the terminal ln linear
decline
for the metabolite must parallel the parent because final disposition
of the
metabolite will be dependent on its formation rate not its elimination
rate.
The larger AUC for metabolite is explained by a smaller volume of
distribution for it. As for the IV data, I might suggest that you are
actually measuring the distribution rate of the parent drug and not the
terminal half life which I would expect is 40 minutes. In conclusion I
imagine your drug has a very rapid distribution and elimination, and
when
given IV you did not actually measure the parent drug's terminal
disposition. It is possible for the metabolite to have a longer T-half
than
the parent but I suspect if sampling were to continue for a longer time
period they would parallel. If I knew what doses (IV and PO) as well
as the
assay limits and sampling scheme, my speculations could be evaluated
more
objectively.
Art Straughn, Pharm.D.
Professor and Director
Drug Research Laboratory
University of Tennessee
874 Union Ave
Suite 5P
Memphis, TN 38163
E-mail: ASTRAUGHN.-a-.UTMEM.EDU
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Hello Ananda
I think much depends on the physicochemical properties (Solubility, pKa,
binding characteristics) of your drug. If the drug were to precipitate
in
the git or bind extensively to the mucosa then you might be able to
justify
your findings. Then if you calculate MRT it is the MAT (Mean Absorption
Time) which is the main contributing factor.
Venkatesh Atul Bhattaram
Post-doctoral Fellow
University of Florida
Gainesville-32610
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dear ananda,
Apart from the possibility of having flip flop kinetics wherein the
rate of absorption is slower than the rate of elimination hence first
phase will be representative of the elimination and not the absorption.
Second possibility i predict is a strong entero-hepatic circulation of
the metabolite after peroral administration that may result in higher
AUC and longer elimination halflife.The extent of that will be
substantially less or negligible when given by IV.
Your querry can be answered more precisely if you can share
physicochemical characteristics of drug and metabolite ,if identified.
( Hydrophillic or Lippophilic).
Hope it makes sense.
Kind regards,
Pradeep S. Bhadauria
Ranbaxy research Laboratories.
INDIA.
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In case of an entero-hepatic cycle you should have a significant PK
profile
as you should see the reabsorption process on the graph.
Ananda, as you say that iv T-halves are not the same between the drug
and
its metabolite do you mean that the difference is statistically
significant
?
Regards,
Frederic
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