Novel approaches to animal and human pharmacology: Pharmacokinetic imaging with 195mPt-cisplatin and 195mPt-carboplatin and correlative functional imaging of the pathophysiological status of tumors

Pharmacokinetic imaging (the measurement of the time course of a drug at a target site), when combined with functional imaging (the measurement of the functional properties of the host's target site), provide the key elements needed to understand whether a drug can reach its desired target site (tumor) and whether it will do so at rates and in amounts that will make that drug effective in that individual. We have now developed a method that allows for the concurrent measurement of all the three spaces of tumors: the cellular space can be studied by using the 195mPt-labeled drugs, the vascular space by using 99mTc-RBC's and the sum of all extracellular spaces by using 111In-DTPA. Performing such imaging studies in such an order allows for concurrent measurements, in as much as the energy window of the gamma camera can be moved from 195mPt (mostly 66-77 keV) to 99mTc (centred on 141 keV) to 111In (energies above 180 keV). Studies in an animal tumor model have shown that the parameters of cisplatin or of carboplatin can be estimated from the imaging data following administration of the 195mPt-labeled drugs. As a next step, the functional status of tumors is of particular importance, given that changes in the tumour's pathophysiology will modify greatly the ability of drugs to be delivered to that target site - and hence, to be effective as antitumour agents. This is especially critical for drugs whose tumor targeting is governed by first passage phenomena, such as cisplatin and 5-FU, but very different for drugs whose targeting is governed by slow diffusion processes. These functional studies allow the direct measurement of the relative contributions that the well vascularized regions, the poorly vascularized regions, and the non-vascularized regions will make in allowing drugs to be targeted to tumor cells, as well as of the relative proportion of the vascular and the IF spaces in such regions. A new approach to chemotherapeutic planning is proposed: the use of radiolabeled drug, in trace (radiopharmaceutical) doses, may allow an estimate of which fraction of that drug will target the desired effector sites. Such knowledge can then be used to select the methods of drug administration that is likely to be the most effective for optimizing drug delivery, and, thereby, enhancing the therapeutic effectiveness of that drug. This use of radiopharmaceuticals for drug monitoring (Pharmacokinetic Imaging) complements the current uses of radiopharmaceuticals for diagnostic studies and for delivery of therapeutic uses. (author)