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Dear Pharmacokineticists,
Recently I was assigned to study the pharmacokinetics of a novel
compound in the rat model and to get a preliminary idea of its
kinetics.
I administered iv-bolus and oral doses of the drug to SD rats ( the
same batch of rats were divided in two groups, one for iv-study and
the other group for oral study). I looked at three different doses:
0.15 mmol/Kg, 0.13 mmol/Kg and 0.1 mmol/Kg and extracted whole blood
for HPLC analysis.
I knew that compound was lipophilic and had about 70% binding to
serum albumin from in vitro studies, it was also very stable upon
incubation with plasma and liver microsomes. In fact, we anticipated
that it would have an oral bioavailability of almost 1 or close to 1.
The results of the studies were as following:
1. Bioavailability of 150% at 0.15 mmol/Kg
2. Bioavailability of 75% at 0.13 mmol/Kg
3. Bioavailability of 30% at 0.1 mmol/Kg
I am much puzzled by these results and would appreciate any comments
that might help to clarify the following points for me:
At first a bioavailability of 150% was surprising. Secondly, why
would it change so drastically by reducing the dose by only about 14%
and 33% of the origianl dose respectively. How should one measure the
oral bioavailability of a compound like this?
I would also appreciate if you have any comments about pros and cons
of using whole blood rather than serum or plasma for extraction of
the compounds.
Thank you
Parsiwa.at.hotmail.com
[Saturable kinetics? Is a plot of AUC versus dose linear/straight line? - db]
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The following message was posted to: PharmPK
I have experience in measuring bioavailability in different laboratory
animals. I would suggest you to take much bigger animal such as rabbit.
That might answer some of your queries because it may be the binding or
/and molecular composition of the novel compound . Did you look at the
literature for the bioavailability of any other compound which is similar
or close to your compound?
Beside this, There are other possible reasons since we don't have much of
your methodology. What was the number of rats in a group (statistical
significance of your results)? Why did you take whole blood not just the
plasma/serum?
I would apprecite if you could provide us the answer to these questions.
Thanks
Naushad
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Is the compound stable in 0.1N HCl, acidic environment in the
stomach? May be it is little acid labile(less than full dose
reach the intestine) and significant biliary excretion/reabsorption.
Bill Tong
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The following message was posted to: PharmPK
Thank you for your comment.
I am not too sure about the acidic stability of this compound and I
will have to look at that, thanks for your suggestion.
Thank you
Parsiwa
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The following message was posted to: PharmPK
I am particularly interested in how you are obtaining a bioavailability
greater than 1. Might there be a problem of solubility in your iv
preparation for your high dose, resulting in a decrease in the actual
administered iv dose?
Also, as mentioned previously - is enterohepatic recirculation a
possibility? What is the compound's MW? How does the PK profile look?
Perhaps doing some biliary cannulations in your rats and collection of
bile might provide some insight.
David Jaworowicz
Cognigen Corporation
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What was the vehicle and the solubility of your drug in this vehicle? Do you
suspect the drug had the potential to precipitate out of solution.
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Bioavailability more than 1 can not be explained on the basis of
enterohepatic circulation(EC). In my opinion as first step of EC is
cojugation reaction which is a saturable process so the extent of EC
should be quantitatively more at lower dose level but the
bioavailability at lower dose range is 33 & 70%. in short if EC is
culprit for this phenomenon at lower dose level also F should be more
than one. Although as said earlier two requrements are there for a
compound to undergo EC are 1) high MW 2)high lipophilicity but
experimental errors can also be there .
Solvent used to dissolve the compound & its physical stability after
dilution can make the picture clear.Rarely , there can be PK related
factors playing a role.
Pradeep S. Bhadauria
Torrent Research Centre
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)