Fluoropyrimidine metabolism

While in vivo 19F MR has provided unique insight into fluoropyrimidine metabolism, most spectroscopic studies have limited numbers of patients and thus are subject to potential bias due to the variability in individual biometabolism. The small number of subjects can further limit generalization of the results to a larger population. In addition, studies of deep tissues or small lesions are challenging using 19F MR spectroscopy because they cannot be adequately evaluated using surface coil techniques and the low signal levels preclude use of a volume coil. 

Fig. 3. Metabolism of the fluoropyrimidines dTMP = deoxythymidine monophosphate, dUMP = deoxyuridine monophosphate, FdUDP = fluorodeoxyuridine diphosphate, FdUMP - fluoro-deoxyuridine monophosphate, FdUTP = fluorodeoxyuridine triphosphate, FU-DNA= fluorouracil-deoxyribonucleic acid, FUDP = fluorouracil diphosphate, FUMP = fluorouracil monophosphate, FU-RNA = fluorouracil-ribonucleic acid, FUTP = fluorouracil triphosphate.

The recent availability of oral formulations of 5-FU involving the ability to modulate the anabolic and catabolic metabolism of 5-FU with LV and dihydropyrimidine dehydrogenase (DPD) inhibitors has provided a substantial improvement in the ease of administration and may probably improve the efficacy of fluoropyrimidine-induced radiosensitization. Such oral fluoropyrimidines include UFT (uracil tegafur) plus oral LV (Orzel ), an oral DPD-inhibitory fluoropyrimidine (DIF), and capecitabine (Xeloda Roche). 

R. Martino, M. Malet-Martino, V. Gilard, Fluorine nuclear magnetic resonance, a privileged tool for metabolic studies of fluoropyrimidine drugs, Curr. Drug Metab. 1 (2000) 271-303. 

Capecitabine is a fluoropyrimidine carbamate prodrug with 70-80% oral bioavailability. It undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5 -deoxy-5-fluorocytidine. This is converted to 5 -deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5 -deoxy-5-fluorouridine metabolite is then hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer. 

Source Reprinted with permission from Malet-Martino, M., Cilard, V., Desmoulin, F., and Martino, R. Fluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs, Clin. Chim. Acta (2006) 366, 61-73. Copyright (2006) Elsevier.)... 

A number of excellent review articles exist, including several that explain MR spectroscopy and detail the impact of MR spectroscopy in drug design and in preclinical studies, and others that provide overviews of human in vivo metabolism and pharmacokinetics measured by 19F MR in fluoropyrimidine compounds as well as in psychotropic compounds [1, 3-5, 7-10, 59, 60-63], In keeping with other facets of drug development, the number of 19F MR clinical investigations is much smaller than the number of animal model, specimen, cell line, or solution experiments. 

---