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We are evaluating alterations in pharmacokinetics of the anticancer drug
when coadministered with chemosensitizers for overcoming P-glycoprotein
mediated multidrug resistance in solid tumors. As controls, we are using
normal (tumor-free), and MDR knockout mice. It is likely that the tumor
itself can alter anticancer drug PK. If anybody in this group has
experience in this area (alteration of PK caused by tumors), their input
into the design of such experiments would be most welcome and looked
forward to.
Regards,
Rajesh Krishna
BC Cancer Agency
http://members.tripod.com/~rkrishna/index.html
[Liposome Drug Delivery Systems Home Page]
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Dear Dr. Krishna:
We have been studying and documenting the effect of modulators on the PK of
5-FU in solid tumors (especially breast and colon in humans), and in several
rat models. I will be glad to discuss this directly. My e-mail address,
telephones and faxes are listed below.
Let me begin by referring you to a paper we presented in 1995 at
the AACR meeting entitled: "Pharmacokinetic Guidance of Drug
Modulation: Initial studies with 5-fluorouracil" (#2141). We have
a number of such studies, which we hope to publish shortly in full
detail.
The main thrust of our approach is the use of noninvasive methods
(NMR spectroscopy and nuclear imaging) to monitor drug
pharmacokinetics at their target sites, rather than inferring what
might happen based on blood data. The latter do not yield reliable
information on the time course of drugs at their target sites, and we
had shown (J. Pharm. Sci. 53:873-877, 1986) that interanimal
variations (and obviously, interpatient variations) will cover subtle
changes unless the same individual can be used as his/her own
control. Hence, noninvasie methods are absolutely required.
Sincerely
=========================================================================| Professor Walter Wolf, Ph.D. E-Mail: wwolfw.-a-.hsc.usc.edu |
| Director, Pharmacokinetic Imaging Program |
| Department of Pharmaceutical Sciences Telephone: 213-342-1405 |
| University of Southern California Fax: 213-342-9804 |
| 1985 Zonal Ave., Los Angeles, CA 90033 |
| |
| Center for Noninvasive Pharmacology, Los Angeles Oncologic Institute |
| MRI at St. Vincent Medical Center Telephone: 213-484-7235 |
| 2131 Third St., Los Angeles, CA 90057 Fax: 213-484-7447 |
========================================================================------------------------------
Date: Mon, 12 May 1997 15:56:52 -0500
From: Stephen Lowis
Subject: Altered PK by solid tumor properties
Rajesh,
A few years ago I did some studies on etoposide in children with
Cyclosporin A as a modifier of PGP, and found significant changes in
clearance. I gather this is a fairly well described effect. I am unclear
why you think tumours in mice might be altering drug PK themselves, unless
you are allowing them to reach enormous proportions.
Regards,
Stephen Lowis
Department of Paediatric Oncology,
Bristol Royal Hospital fro Sick Children
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Stephen:
Thanks for your note. Yes, it is a well described effect that inhibitors
or more appropriately, modulators of PGP alter significantly the
anticancer drug PK, particularly clearance, when coadministered for MDR
reversal. However, it is possible that the tumor by itself can alter the
PK of the anticancer drug (healthy vs tumor bearing animals) by altering
drug metabolism. We are studying the effects of PSC 833 on doxorubicin PK
and the possible effects of PSC 833 on the metabolites of DOX in solid
tumor bearing experimental animals (~100-200 mg tumors) - and would need
to delineate the effects of the tumor itself (effects of the tumor
vasculature, angiogenesis, microvascular environment on drug uptake and
disposition as well as to address the issue of metabolism in tumors).
Regards,
Rajesh
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