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An ester prodrug's standard curve is to be generated
in animal and human plasma. How do we do it? Do we
make a standard curve of the acid metabolite or add an
esterase inhibitor to the plasma? Can we spike the
plasma with the ester and precipitate the protein at a
fixed time (or immediately after spiking), before its
complete conversion to the acid? Do we need to
determine the rate of conversion from the ester to the
acid in different plasma here? Any advise or
suggestions will be highly appreciated.
Thanks
Ananda
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I think the answer to your question depends to some extent on the
properties of the ester. Does the ester have any biological activity?
How stable is it in spiked plasma? How does the concentration-time
profile of the metabolite (your drug) look like? And what do you know
about the effect-concentration relationship of your drug and the ester?
I know of another ester (artesunate) that is rapidly converted to the
drug (dihydroartemisinin). Both the ester and the resulting drug have
biological activity (antimalarial). What people do is to determine the
concentration of both compounds, although the ester obviously is usually
gone within a couple of hours.
I guess the question is whether you need to know the ester
concentrations in order to get a better understanding of your drug
exposure and effect.
Toufigh Gordi
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Dear Ananda,
Toufigh Gordi says "I know of another ester (artesunate) that is
rapidly converted to the drug (dihydroartemisinin). Both the ester and
the resulting drug have biological activity (antimalarial). What people
do is to determine the concentration of both compounds, although the
ester obviously is usually
gone within a couple of hours"
He is right in this context. At the same time I feel you need to
generate
linearity for both ester and metabolite separately. For ester, you can
add
esterase inhibitor in excess and can generate the linearity for pro drug
alone. And also you can generate another linearity separately with acid
metabolite for the analysis of that.
Regards,
KANTHI KIRAN V.S. VARANASI, M.Pharm, MBA
Senior Research Scientist,
Pharmacokinetics and Drug Metabolism Department,
Glenmark Pharmaceuticals LTD.
INDIA.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)