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The following message was posted to: PharmPK
Hello
If the PK of a drug in blood has a different profile shape than the PK
measured in tumour (i.e. tumour PK shows longer terminal half life,
flatter peak at early time points) then does that necessarily mean that
its distribution into tumour is not perfusion limited, but diffusion
limited? (or even actively transported...) It's not that it's parallel
and just shifted to the right, in fact drug seems to appear quickly in
the tumour but then its profile remains relatively flat compared to the
blood PK profile.
So when trying to model the two profiles, in an attempt to make it
semi-physiological, I use the following term for defining the rate of
drug transfer into tumour: Q*Ac/Kp where Q is (in theory) the tumour
blood flow, Ac is the amount of drug in the central compartment (ie
blood) and Kp is the observed ratio AUCtumour/AUCblood. Now the thing
is, clearly the ratio between the tumour concentration and blood
concentration appears to change with time (I do not know the conc ratio
at steady state). But it would seem wrong (to me) to have a Kp term that
changes, and since Q will be constant, I obviously need to 'change' the
tumour distribution some other way. Any suggestions? I still need rapid
distribution into tumour so perhaps a saturable clearance out of tumour
(is this physiologically realistic?)
Any help would be much appreciated, I am fairly inexperienced with this
game!
Kathryn
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The following message was posted to: PharmPK
Kathryn:
Active transport is certainly part of the determinants of drugs from the vascular space into the cellular space. Indeed, such transport can be significantly modulated by other drugs, and that may need to be taken into account. At the same time, you have to remember that in a solid tumor you have to consider at least 3 physiological compartments: the vascular space, the interstitial fluid space (aka microenvironment) and the intracellular space(s).
How do you measure the PK in the tumor? In our studies measuring changes in tumoral blood flow, the critical measurements are within the first minute or two, and when we use DCE-MRI, we can collect 120 time points (1 each second) during that time period.
Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California
1985 Zonal Ave., Los Angeles, 90089-9121
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The following message was posted to: PharmPK
Dear Kathryn,
You may find the following article of interest, it deals with brain rather than tumor penetration but the principles should apply to various types of tissues. There may be articles out there more specific to tumors.
Kp is essentially an equilibrium parameter, what you describe seems to indicate your compound might never be at equilibrium between blood and tissue, the article could give you clues as to why that may be (without having necessarily diffusion limitation, nor active mechanisms involved).
Liu et al., JPET (2005), 313(3): 1254-1262
Patrice
--
Patrice Larger
Pharmacokinetics, Metabolism & Dynamics
Translational Sciences & Pharmacokinetics Dpt
patrice.larger.aaa.rottapharm.com
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I think there may be the matter of efflux transporters. If I m not wrong then some of the efflux transpoters are expressed abnormally in tumor tissue with compare to normal tissues.e.g. MDR1. I dont know much about tumor pk, but one should focus on Vd (here for interstitial fluid) and Blood flow .
Thanks in advace for sharing some views.. Mitul Patel
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The following message was posted to: PharmPK
Mitul and all:
When I had mentioned active transport between the interstitial fluid and the tumor cell, that naturally included both influx and efflux transporters.
And I also agree with Patrice comment that many drugs may never be at equilibrium in blood. The competition between tumor targeting, uptake at non tumor tissues, and elimination, may result in what we had called a first-passage driven tumor uptake. This was clearly shown in our paper in Cancer Research:
J. Shani et al: Noninvasive Monitoring of Drug Biodistribution and Metabolism: Studies with Intraarterial Pt-195m-Cisplatin. Cancer Research 49, 1877-1881, 1989
-- Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California
1985 Zonal Ave., Los Angeles, 90089-9121
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