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I am working on a problem that has me stumped. We did a study in mice
(oral vs ip) once daily dosing for 28 days equal doses. The
bioavailability after oral administration is about 50%. The drug
requires metabolic activation for activity (not hepatic, but
intra-tumor metabolism). The oral pd activity in reducing tumor growth
was equal to or greater than the ip route of administration. The
results are pretty impressive for the oral route but less so than
the ip route. Is it possible the ip route (which is usually assumed to
have bioavailability similar to iv) has lower bioavailability than the
oral route?
Does anyone have any ideas why this is?
Thanks,
Peter Bonate
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One of several possibilities:
What is the reason for 50% bioavailability, is it pre-systemic
metabolism?
If so, have you considered the role of metabolites, if any via oral and
ip
routes.
Regards,
Joga Gobburu
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What about the drug getting precipitated when administered IP? Less of
it is getting into the systemic circulation over time compared with the
same dose administered PO.
Ananda
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Peter,
one possible explanation would be that the release of the active (after
ip
dosing) does not allow higher concentrations than the one observed per
po
route. In this hypothesis the ip route acting as a reservoir would
release
the active at a such slow rate that the amount of drug reaching the
tumor is
never higher per ip than per po.
Another explanation could be that the metabolism you are describing in
the
tumor is saturable. Did you check this phenomenon with different doses ?
Hope this helps
Regards
Frederic
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Peter,
Do you have any PK data available after ip vs iv administration?
I would question the assumption of complete bioavailability after ip.
I do have some experience with a high hepatic extraction compound in
the rat
(i.e. >70%), where
ip bioavailability was approx. 15%. By the way, this created animated
discussions with some pharmacologists, who would usually consider ip as
a
surrogate for iv.
Kind regards,
Henri Merdjan
+33 (0)1 45 78 06 72 (GMT+1hr)
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I was wondering that you say Oral bioavailability is 50% is it against
the IV administration, if yes than you should have the bioavailability
through ip route as well. Bioavailability through ip can be less than
100% and is not always like IV. But is it the bioavailability problem.
It seems to have something to do with the rate of its availability to
the tumour site, if it is purely tumour site activation, as in case of
IP it may be available quickly thus causing saturation of metabolic
enzymes needed for activation inside the tumour. Just a thought. Hope
this helps.
Manoj Khurana
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I don't know of many drug metabolizing enzyme systems that are specific
to
tumor cells. There could be increased enzymatic conversion of prodrug to
active drug in the gut, therefore oral PD is superior. Also, it was my
understanding that IP is subject to some first-pass effects.
Shelly Dunnington R.Ph., Ph.D.
DunningtonShelly.-a-.praintl.com
913-577-2767
16400 College Blvd.
Lenexa, KS 66219
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