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Dear all,
We determined the fraction absorbed (Fa) in rat after oral
administration comparing the obtained AUC with the AUC obtained after
intravenous administration (n=3 for both iv and oral administration).
The Fa obtained was 60% (range 50-70%).
After oral administration in bile duct cannulated (BDC) rat (at the
same dose of the previous oral dose) of the radiolabelled version of
the compound, a mean of at least 20% of the dose was absorbed by
these animals, as judged by the amounts of radioactive drug-related
material eliminated in bile and urine, and radioactivity in the
residual carcass (minus the gastrointestinal tract). Considering
that in this case we are speaking of drug-related material we should
have a higher value than 60% and not lower.
Similar results were obtained in other two compounds with similar
structures.
Could someone try give me an explanation of these results?
Other info that could be helpful is that the blood clearance is low
to moderate in rat.
I've thought to a mechanism of direct gut secretion (but 40 %???) or
a lung first pass effect (overestimation of AUC after IV
administration ... but the compound is metabolically stable!).
Thanks in advance
Best regards,
Massimo Trofino
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I'm sorry I've realised that there was an errore in my previous
messagge (I wrote overestimation instead of underestimation see below):
Dear all,
....
I've thought to a mechanism of direct gut secretion (but 40 %???) or
a lung first pass effect (overestimation UNDERESTIMATION of AUC after
IV administration ... but the compound is metabolically stable).
sorry
Best regards,
Massimo Trofino
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The following message was posted to: PharmPK
Massimo,
I believe that removal of the secretion of bile salts in the small
intestine will decrease the oral absorption of your molecules, if they
are fairly nonpolar. Hakk et al. found that the oral absorption of a
polybrominated diphenyl ether compound was greatly reduced in bile duct
cannulated rats compared with conventional rats (Hakk H, Larsen G,
Klasson-Wehler E 2002, Tissue disposition, excretion and metabolism of
2,2',4,4'5-pentabromodiphenyl ether (BDE-99) in the male Sprague-Dawley
rat. Xenobiotica 32: 369-382).
Regards,
Ling-Jen Chen Ferguson
Lovelace Respiratory Research Institute
Email: ljferguson.-at-.lrri.org
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