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Hello
I would like to know what is the interest in
investigating the tissue distribution of a compound in
the spleen?
Regards,
Leandro.
UFRGS, Brazil.
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The following message was posted to: PharmPK
Leandro:
The ultimate effect of a drug is closely associated with both its
concentration and its rate of uptake at its target site. Thus,
knowledge of the time course of a drug at a given target, be it an
effector site or a toxicity site, is critical in understanding why a
drug will (or will not) be effective in a given patient, and to develop
proper strategies for optimizing pharmacotherapy.
Knowledge of drug levels in blood is useful, but is in many instances
of limited value in understanding target concentration. As a
distinguished colleague of mine commented many years ago: "Measuring
drugs in blood is like a policeman watching who does in and out of a
house. But it does not allow him to know precisely what is going on in
the bedroom!".
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
90089-9121
E-Mail: wwolfw.-at-.usc.edu
Telephone: 323-442-1405
Fax: 323-442-9804
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Dear Dr. Tasso
You asked about localization of drugs in the spleen.
Certainly, it is important for several reasons.
Efforts to localize drugs in a whole organ or chunks of it, however,
are not enough and likely to fail in important parts, since the
radioactive label may pertain to blood, extracellular fluid, or any of
the tissues.
Each organ is composed of different cell populations with different
functions. It is not enough to declare that a compound is in the
brainEor not in the brainE in the pituitaryE in the pancreasE
or in the spleenE
We demonstrated vitamin D concentration in particular cells in the
spleen in the red pulp and in the marginal zone of follicles, while
absent in lymphocytes of the white pulp.
Tissue and cellular localization provide important clues for function.
Please, see for yourself in the attached autoradiogram (from Stumpf et
al., Histochemistry (1990)94:121-125).
From this fact that usually not all cell types of a given organ are
targets and frequently target cells may constitute a subpopulation only
of the total, it follows that grinding up an organ or chunk of it, or
scanning from the outside, most likely will miss some or all of the
specific targets.
This subject matter is discussed in detail in a recently published book:
Drug Localization in Tissues and Cells. 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. $
164.--.
Distributed by
UNC Student Stores
Chapel Hill, NC 27599
Order inquiries to
Erica Eisdorfer
Phone: (919) 962-2420
Fax: (919) 962-9661
E-mail: eisdorfer.aaa.unc.edu
The autoradiogram in the attachment depicts the localization of
radiolabeled compound after injection of 3H-1,25(OH)2vitamin D3. On top
is a portion of white pulp, below is the marginal zone and red pulp
with specific cells (certain macrophages) that concentrate and retain
the drug. [Not attached - db]
Best regards, Walter E. Stumpf
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The following message was posted to: PharmPK
Hello Leandro,
If the time course of drug concentration in the spleen is very
different to that in blood, then tissue distribution data can help you
determine the kinetic profile. This has been observed in the lymphoid
organs of rats for a number of immunosuppressants. I've listed a few
references.
1. Kawai R, Lemaire M, Steimer JL, Bruelisauer A, Niederberger W,
Rowland M. Physiologically based pharmacokinetic study on a cyclosporin
derivative, SDZ IMM 125. Journal of Pharmacokinetics and
Biopharmaceutics 1994; 22:327-365.
2. Kawai R, Matthew D, Tanaka C, Rowland M. Physiologically based
pharmacokinetics of cyclosporin A: extension to tissue distribution
kinetics in rats and scale-up to man. Journal of Pharmacology and
Experimental Therapeutics 1998; 287:457-468.
3. Tanaka C, Kawai R, Rowland M. Physiologically based pharmacokinetics
of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats.
Journal of Pharmacokinetics and Biopharmaceutics 1999; 27:597-623.
4. Tanaka C, Kawai R, Rowland M. Dose-dependent pharmacokinetics of
cyclosporin A in rats:events in tissues. Drug Metabolism and
Disposition 2000; 28:582-589.
Best Regards
Alex
A.J.MacDonald Ph.D
F. Hoffmann-La Roche Ltd
Pharma Research
Non-Clinical Safety
Modelling and Simulation
PRNS, 70/132
CH-4070 Basel Switzerland
Tel: ++41 61 68 84098
Fax: ++41 61 68 82066
alexander.macdonald.aaa.roche.com
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