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Hi,
We recently conducted a discovery PK study in rat dosing via IV, IP,
and PO. Turns out the absolute bioavailability for PO dosing was 3
times of IP dosing (75% vs 25%).
Could anyone provide some insight into how this could have happened?
One would assume that by dosing IP, loss of drug due to incomplete
absorption is avoided and bioavailability would be higher than PO
dosing.
Thanks for any suggestions,
JS
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Hi
Whether the doses you tried at by the iv, ip and po were at the same
dose level. I think it is also important the comparison should be done
at low doses
If you have tried a higher dose in po compared to ip, and the molecule
doesn't follow a linear kinetics at higher doses, you may get more
exposure than ip
Another explanation which comes to my mind is precipitation of the NCE
in intraperitoneal cavity, whereas it is not happening in p.o scenario.
comments are welcome.
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The following message was posted to: PharmPK
What is the pH optimum for your drug absorption? PO exposes the drug to
extremely acidic and then basic conditions rather than neutral, or
close to
it. It may be that your drug is absorbed better in acidic or relatively
basic conditions.
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Hi,
Did you ever check stability - solubility for your formulations? More
specifically, did you checked about the behaviour of your formulation
at the site of injection (IP injection).
Surprisingly we have already experienced 150% bioavailability of some
oral formulations!!! We do much better than the chemists since we
create material.....
In reality, this was mainly due to re-precipitation of IV formulation
when injected to the rats.
Hope that this might help you for further investigations.
Jean
Oroxcell
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The following message was posted to: PharmPK
Dear All,
I would certainly agree with Vinu's explanation relating to the
precipitation at the injection point. If the release percentage was
not higher than 25% at the end of the study one should think that
roughly 75% of the drug remains entrapped in the ip cavity.
How long was the study? Were the last plasma concentrations
significant after iv? po? ip?
Cheers,
Frederic
Frederic Doc
fdoc.-at-.acriter-consulting.com
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Dear JS,
Although in initial pharmacological studies there is an intuitive
assumption that an ip administration is almost equivalent to iv
administration, it may be very much not so in the case of medications
with poor membrane permeability. We have just published a study
(Hoffman, A. et al Carbamoylphosphonate matrix metalloproteinase
inhibitors 6: cis-2-Aminocyclohexylcarbamoylphosphonic acid, a novel
orally active antimetastatic matrix metalloproteinase-2 selective
inhibitorsynthesis and pharmacodynamic and pharmacokinetic analysis.
J Med Chem. 2008 Mar 13;51(5):1406-14. Epub 2008 Feb 8.) were the ip
administration provide input of the drug for about 48 hr after
administration, while the iv half life is about 1 hr.
It could be reduced solubility or poor permeability, but it tells us
to follow-up on the concentration (in blood or urine) for long enough
time period to account for the mass-balance.
Best regards
Amnon
Prof. Amnon Hoffman
Chairman, Dept. of Pharmaceutics
Head, Clinical Pharmacy Program
School of Pharmacy
Faculty of Medicine
The Hebrew University of Jerusalem
POB 12065, Jerusalem 91120 Israel
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Hi, JS:
Are the doses same between IP and PO (nonlinearity)? How about the
solubility of this compound (pH-dependent)?
GS
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Dear JS,
There could be reasons which may relate with pH solubility profile and
bio-pharmaceutical properties of your compound. Providing more
information like compound nature (free acid/base versus salt), dose
and dosing vehicle and form (solution/suspension), would have had more
clearer picture to readers of this forum.
Oral delivery of compounds subject them to a range of physiolgical pH
scenario as compared to IP dposing where they have to partition from
intraperitoneal membrane at or around neutral pH to systemic
circulation. Take example 1, if your drug is a HCl salt, it will
remain soluble at upper GIT (not precisely the site of passive
absorption) but tend to precipiate in intestinal fluid, where if it
may form a transient solid phase (which may exepedite or delay
dissolution) and may get solubilized faster or slower. IP dosing may
behave differently as the drug will not be having an ambience of
different physiological pH to dissolve/redissolve type of event. So if
you start with a suspension of crystalline drug, it will have to
dissolve in order to get through. Take example 2, if your drug is a
solution, but at injection site, gets precipiated, may again take
longer to redissolve and get partitioned.
Therefore, bio-pharmaceutical perspectives may partially or in
majority may dictate the observations recorded at your end.
regards
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