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Hi! All
We are working on a new antidepressant (A) which has a
bioavailability of 0.27% in rats. We tried to evaluate the role of
different organs in the low bioavailability by administering the drug
by different routes. If we consider the bioavailability by
intravenous (iv) route as 100%, absolute bioavailability was 0.27%,
ip vs iv was 45% and oral vs ip was 1%. It indicates that either the
drug is poorly absorbed or undergoing metabolism in the git. The drug
however undergoes conversion to a metabolite (carbonyl group
reduction due to oxidoreductases) in the S9 fraction of rat
intestine. It is stable in gi contents. We analysed portal and venous
samples after a single oral dose in rats to get an idea of the amount
of drug being actually absorbed. We applied the models suggested by
Dr. Youngill Kwon (Pharm. Research Vol 13, No. 4, 1996 pg 566-569)
and Dr. Kiyoshi Yamaoka in Drug Metabolism and disposition ( Vol 24,
No. 2, pg 216-220). The former indicates 50% drug absorption while
the latter indicates only 2% drug absorption. Which model should be
used? The total % of dose excreted in feces is about 18% of which
parent compound contributes to just 25% and the rest is by the other
metabolites excreted in bile (which we have confirmed). Although a
metabolite was observed in portal vein samples also its concentration
is not that significant to really account for such a loss.
Suggestions are welcome.
R. C. GUPTA
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)