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The following message was posted to: PharmPK
Recently (August 6), Dr. Subramanian posed very important questions
about “PharmPK Accuracy of current methods of predicting PK parameters”:
a) What is the range of accuracy of "purely" in silico methods
b) What is accuracy range of in vitro methods
c) How well does animal PK correlate with human PK.
Any pointers will be highly appreciated.”
Dr. Subramanian told me that he received two replies to his query and
that “there is not a whole lot of information in them unfortunately.”
How are the results and predictions of the above IN VITRO procedures
currently being validated? How can or could they be validated? These
questions demand answers.
One important approach would be IN VIVO localization with TARGET
identification and target binding kinetics.
Is somebody doing it?
When problems related to IN VIVO localization of drugs in tissues
surfaced during the exchange of letters on this website, no
satisfactory answers were provided to my queries (January 2000; March
Current IN VIVO localization procedures include radio-assay-HPLC, whole
body autoradiography, and non-invasive imaging. The results from these
approaches are important. But how informative are they really? Are
extrapolations from kinetics of blood and non-target tissue levels to
kinetics of target tissues justified in view of evidence that data
about target cell populations may differ considerably from those of
blood levels and of non-target tissues? Even among different target
tissues, kinetics may be target specific.
At the core of the debate are questions of SENSITIVITY and RESOLUTION,
and the related limitations of information. I have maintained and
demonstrated that in conventional ADME studies information on drug
localization in tissues may be deficient. There may be false negatives
galore. Target sites of action with high affinity and characteristic
low capacity of receptor binding may not be recognized. This is
contrary to the general assumption that the tissue localization (with
the generalizing THE) can be accomplished through radio-assays, whole
body autoradiography, and/or nuclear imaging. It cannot – or only to a
very limited degree in exceptional cases.
With current in vivo distribution studies, important information may
remain hidden that is needed for the selection of a new drug,
identification of sites and mechanisms of action, prediction and
toxicity. Since the selections of an agent are strongly influenced by
results obtained from radio-assays, whole body autoradiography, in vivo
scanning tests, and in vitro procedures, assessment of the utility of
each single approach is important.
Therefore, to be able to validate the in vitro procedures mentioned by
Dr. Subramanian, in vivo target identification and related kinetics
would be paramount. Of course, the usefulness of the in vivo
procedures, their resolution and sensitivity, would need to be
validated before as well.
This subject matter is discussed in a recently published book that
details Receptor Micro-Autoradiography and includes comparative studies:
Drug Localization in Tissues and Cells. Receptor Microscopic
Author: Walter E Stumpf.
ISBN 0-9740515-0-0. Library of Congress Control Number 2003105179.
IDDC-Press, Chapel Hill, NC. July 2003. 170 pages with color plates. $
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