Back to the Top
Dear All
In one of PK study in mice we are getting Oral Cmax concentration
more than the Cp0 conc. which we can get by extrapolating i.v.
points. The compound is having very high distribution characteristics
in tissues. Any one can explain this phenomenon?
Jakir
[Same dose? Single dose? - db]
Back to the Top
The following message was posted to: PharmPK At 09:10 AM 9/15/02,
Jakir Pinjari wrote:
>In one of PK study in mice we are getting Oral Cmax concentration
>more than the Cp0 conc. which we can get by extrapolating i.v.
>points. The compound is having very high distribution
>characteristics in tissues. Any one can explain this phenomenon?
>
More information is needed - can you be specific about the dose
amounts and formulations? Was the oral dose a suspension or solution,
and was the IV dose a bolus, as it sounds, or an infusion?
Also, perhaps a little more information about the compound, e.g.,
protein binding, clearance pathways, etc.?
Back to the Top
Jakir,
I would suggest two different explanations:
- your PO dose is higher thant the IV one. You should then relate Cp
(Cmax PO and Cp0 IV) to the administered dose before making any conclusion
on your experiments.
- your IV formulation precipitated at injection point resulting in
reduced Cp vs time. Therefore Cp0 extrapolation should be also reduced. What
kind of formulation were used for IV and PO dosings ?
Any additional information about formulations at least should be useful to
answer this question.
Regards,
Frederic
Back to the Top
Dear Jakir,
In absence of information relating to dose/formulation details of IV
and PO formulations, the results obtained may be attributed to
precipitation of the IV formulation upon administration. When
formulating IV dosage forms using surfactants/cosolvents always
ensure that the formulation is dilutable without causing
precipitation of the drug.
It may be advisable to repeat the study using lower doses.
Best Regards,
Sunil V
Lupin Research Park
Back to the Top
Dear Jakir,
Adding one more possibility-
Is your drug an ester/amide containing prodrug, in which case you may
find higher Cmax values (of released drug) with PO route. Ofcourse this
is not be the case if you monitor the prodrug itself.
Regards,
Kasiram.
Back to the Top
Dear Sunil
The formulation used for the intravenous and oral administration is
same( solution) and it is aqueous friendly(No surfactant). So I think
there will be as such no precipitation. Also I have checked the study
at two different doses one lower and one higher in triplicate; I got
reproducible results. Also the oral AUC is higher than the intravenous
AUC, hence the bioavailability is more around (165%). Is there any
different reason for this type of phenomena?
Thanks,
Jakir
Back to the Top
Dear Kasiram-
The drug in present discussion is not a prodrug. I am monitaring the
free drug only by HPLC. Then also I am geting this type of results. Why?
Thanks,
Jakir..
Back to the Top
Lung first-pass effects is a possibility, since the injected drug has
to go thru the lungs first before reaching the general circulation.
Srikumaran K. Melethil, PhD, JD
Professor of Pharmaceutics and Medicine
School of Pharmacy (203B Katz Hall)
5005 Rockhill Road
Kansas City, MO 64110
Back to the Top
What about enterohepatic circulation?
D. Sitar
Back to the Top
Dear Jakir,
I agree with Professor Melethil. We often jump to the conclusion that
after
precipitation, solid drug lodges in lung capillaries. But if the drug
has
two basic nitrogens (even if they are very weak bases), active uptake in
lung appears as a very rapid fall in plasma concentration after a iv
dose.
Then, even the earliest timepoints give a poor prediction of Cp0. I
would
guess that you have a basic drug, and the good news is that it is well
absorbed! Take some lungs and look for drug concentration.
Good luck.
Ted Parton
Celltech R&D,
Slough
UK
Back to the Top
As Daniel mentioned one hypothesis should be the existence of an
enterohepatic cycle. If so you should see a specific PK profile showing
a
reabsorption event.
Regards,
Fred
[A message from the moderator == I'm 'playing' with a new email server
and client so it is difficult to consolidate messages and include the
header information, i.e. the original senders details. There may have
been a few 'consolidated' messages that weren't sent out over the last
week or two. If you think one of your messages suffered this fate feel
free to resend the message (maybe updating the message as necessary) to
PharmPK.-at-.boomer.org - db]
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)