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The pharmacokinetics of 5-fluorouracil (5FU) were studied in vivo in patients with discrete tumors and in rabbits bearing VX2 tumors by using "9F NMR spectroscopy.The human studies were conducted in a 1.5-T Magnetom magnetic resonance imager (Siemens), and the rabbit studies were conducted in a 4.7-T GE/Nicolet 33-cm bore magnet. Free 5FU was detected in the tumors of four of the six patients and in all VX2 tumors but not in normal rabbit tissues. No other metabolites were seen in these tumors, contrary to the extensive catabolism we had previously documented using t9F NMR spectroscopy in both human and animal livers. The tumor pool of free 5FU in those human tumors that trapped 5FU was determined to have a half-life of 0.4-2.1 hr, much longer than expected and significantly longer than the half-life of 5FU in blood (5-15 min), whereas the half-life of trapped 5FU in the VX2 tumors ranged from 1.05 to 1.22 hr. In this initial experience, patient response to chemotherapy may correlate with extent of trapping free 5FU in the human tumors. These studies document that NMR spectroscopy is clinically feasible in vivo, allows noninvasive pharmacokinetic analyses at a drug-target tissue in real time, and may produce therapeutically important information at the time of drug administration. Demonstration of the trapping of 5FU in tumors provides both a model for studying metabolic modulation in experimental tumors (in animals) and a method for testing modulation strategies clinically (in patients).The pharmacokinetic monitoring of drugs in human tumors has been limited by the invasive nature of sample acquisition. Most Prior publications have shown that such noninvasive analyses could be accomplished in mice (2), and we had extended this work to show that the time course of 5FU uptake and catabolism could be monitored in the uninvolved normal liver of cancer patients receiving 5FU as part of their treatment (3). We have now extended such studies by nionitoring the time course of 5FU uptake into tumor tissues in both animal models and patients to assess objectively and individually the degree of drug targeting and metabolism at specific tumor sites.Our results show that the pharmacokinetics of 5FU uptake and metabolism can be measured in vivo in human tumors (breast and colon carcinoma) in real time and that the rabbit VX2 carcinoma (a pharmacological model widely used by others for 5FU-related studies) can serve as an animal model for helping to analyze and understand the data from human tumors. These results show that, contrary to expectations, there is retention ("trapping") of free 5FU in some human tumors. Such tumor trapping of free 5FU may have significant clinical implications for assessing the effectiveness of 5FU treatment, for selection of chemotherapy in individual patients, and for improved evaluation of metabolic modulation of 5FU chemotherapy in vivo. More broadly, these data suggest that in vivo NMRS may have significant potential, both in understanding human biological processes and in guiding th...