Dear all,Back to the Top
The new chemical entity which has low aqeuous
solubility(less than 1ug/ml), but very potent activity
seen by oral route. The predicted log P value is very
high above 5.0.
I am not able to detect the drug in plasma at any time
points after oral administration. I am not able to
understand the drug is very potent but the drug is not
detected in systemic circulation on oral
administration in rats. How to account for
bioavailability of these compounds. Can we take
further developmental activities for this compound. If
we take up, how to account for the bioavailability.
* The drug is detected iv but not by oral route.
* The drug is not a prodrug as per the structure.
* The drug is not detected when adminstered at various
doses. Even in high dose, the drug is not detected in
the systemic circulation.But the potency is very high.
* The confirmation of metabolite is not done. Even if
we consider the chance of presence of metabolite,
which is very active, we are not able to detect the
even the trace of amount of drug. can i have few
points on this.
* So if potency is there by oral route, how to
consider the bioavailabilty. For NCE, the
bioavailability is main criterion. But, inspite of
potency,why systemic circulation, the drug is not
I need some opinion on this.
Potency does not equate with bioavailability.Back to the Top
The medicinal chemist goes to sleep at night dreaming of the lowest
IC50. The DMPK scientist dreams of the highest permeability and longest
half life. The safety person dreams of the compound with no detectable
toxicity. The optimum compound is likely to be one that compromises all
of these. The message here is, you may have to give up potency to get
Have you measured amount of drug recovered in feces and urine? It has to
go somewhere. If a significant amount is not recovered in feces, then I
think you'll have to look for metabolites.
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
Phone: (661) 723-7723
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Mr. Iyar,Back to the Top
It could be possible the drug is getting actively effluxed by the
efflux pumps present in the lumen.
Walt:Back to the Top
The three people you describe - the medicinal chemist, the DMPK
scientist and the safety person - are like the 3 blind men and the
elephant. They only look at one part while ignoring the central and
over-riding need: is the compound EFFECTIVE as a therapeutic agent in
humans? All those measurements are merely aspects of what may be
needed to achieve the highest effectiveness.
Professor Walter Wolf, Ph.D. President, Correlative Imaging Council,
Society of Nuclear Medicine
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
University of Southern California 1985 Zonal Ave., Los Angeles, CA
Dear IyerBack to the Top
What is the activity of the NCE. Is it a hepatoprotectant?
Also as suggested by Walt Woltosz you have to see urine, feces, bile
and metabolism because the NCE has to be somewhere....
Pharmacokinetics and metabolism Division
CDRI, Lucknow- India
vipul kumar gupta
Dear Sivakumar,Back to the Top
The drug you administered will not disappear, it is somewhere, and you
have to find it! Many solutions : it could be metabolized either in gut
or in liver, whether it was effluxed in GI tract (and there you will
find it in feces), may be also distributed largely in a peripheral
I think to find the answer, try to use a radiolabeled form of your
entity there, you will be able to follow the course of your molecule
wherever it goes, and in addition, you can quantify it via its
Makrem BEN REGUIGA,
Pharmacokinetics and Clinical Pharmacy Lab.
Faculty of Pharmacy South Paris - Paris XI - France
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