Hi all,Back to the Top
Has anyone ever experimented on establishing ratios of antitumor drug
concentrations in plasma versus tumors? How reflective are the values?
Does heparin interfere in determining plasma drug levels using HPLC,
especially if sample is hemolysed?
Look forward to some pearls of wisdom.
Satyen
Satyendra:Back to the Top
In answer to your question:
-
Has anyone ever experimented on establishing ratios of antitumor drug
concentrations in plasma versus tumors? How reflective are the values?
-
The short answer is that this is not possible, mainly because of the
following reasons:
1. Solid tumors are heterogeneous. If a patient has several metastases,
each may behave somewhat differently and usually different from that of
the primary.
2. Solid tumors have a significant volume of interstitial fluid space,
whose osmotic pressure can vary significantly over time and between
tumor masses
3. Blood flow to and inside solid tumors can be highly irregular
4. The regulation of antitumor drug uptake and elimination from the
cellular component of solid tumors may vary significantly.
These are some of the reasons why we postulate that the only valid
manner of measuring drug concentration in solid tumors is by direct
measurements of the tumor, and that such measurements need to be done
using noninvasive imaging methods.
--
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.aaa.usc.edu
Telephone: 323-442-1405
Fax: 323-442-9804
Satyen,Back to the Top
I have investigated such ratios in the preclinical setting
previously, and have found several factors:
1) Tumor vasculature can vary greatly from animal to animal (even with
comparable plasma levels) in many tumor xenografts, which leads to
differences in the amount of drug you may see in the tumor tissue. This
I found to be very typical in the preclinical setting.
2) The PK/PD correlation you may try to define will likely depend on
the type of compound involved. If you are looking at a signal
transduction inhibitor, you may find tissue levels (and drug half-life
in the tumor or "effect compartment") to provide some reflection of
antitumor activity. In some other cases with cytotoxics, this may not
hold up depending on the numbers of cells in the growth phase, so to
speak. Also be aware of the time dependence of many of these processes.
Overall, I think you have to be careful about the correlations you try
to establish and make sure that those correlations are explainable and
repeatable.
Just my $0.02 worth.......
Best Regards,
J. Christopher Spell, Ph.D.
Medical Science Liaison - Hematology/Oncology
Global Medical Affairs
Wyeth Pharmaceuticals
Phone: (203) 288-4828
E-mail: spellj2.at.wyeth.com
Dear All,Back to the Top
With all its limitations, it is about time that the experts in this area
think of using microdialysis technique (where feasible clinically and
financially) to answer PK profile in solid tumor. There have been
several
references on this in recent years.
Thanks,
Chandra S. Chaurasia
(The statement made above is purely my opinion)
Dear Satyen,Back to the Top
For anticancer drugs which have cell cycle-specific
mechanism of action, it has been shown that higher
plasma concentrations were associated with greater
antitumor activity and that longer circulation
half-lives were strongly correlated with enhanced
efficacy (Boman et al., 1993, In Old Drugs, New
Therapeutics. Ed Woodle MC and Storm G. I have not
seen any reference trying to establish ratios of
antitumor drug concentrations in plasma and tumors. As
someone mentioned previously tumor vasculatures and
also lymph circulation (interstitial pressure) are
greatly varied among individuals of the same species
which make the task of correlating plasma
concentrations s to tumor concentrations more complex.
I agree with Chandra on micro-dialysis. We recently
used it and got some beautiful data. It is not an easy
technique but it is worth trying.
Rostam
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