5-Fluorouracil, catabolism

Seek K, Riemer S, and Kates R. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. Clin Cancer Res 2005 11 5886-5892. 

Li, C. W., Negendank, W. G., Padavic-Shaller, K. A., et al. (1996) Quantitation of 5-fluorouracil catabolism in human liver in vivo by three-dimensional localized 19F magnetic resonance spectroscopy. Clinical Cancer Research, 2, 339-345. 

Several possible mechanisms of resistance to 5-fluo-rouracU have been identified, including increased synthesis of the target enzyme, altered affinity of thymidy-late synthetase for FdUMP, depletion of enzymes (especially uridine kinase) that activate 5-fluorouracil to nucleotides, an increase in the pool of the normal metabolite deoxyuridylic acid (dUMP), and an increase in the rate of catabolism of 5-fluorouracil. 

Sommadossi JP, Gewirtz DA, Diasio RB et al. Rapid catabolism of 5-fluorouracil in freshly isolated rat hepatocytes as analyzed by high performance liquid chromatography. J Biol Chem 1982 257 8171-8176. 

Like ARA-C, 5-fluorouracil (5-FU) is extensively and variably metabolized among species. The principal catabolic enzyme is dihydropyrimidine dehydrogenase (DPD). Khor et al. (18) examined 5-FU plasma kinetics of mice, rats, and dogs that had been rendered functionally deficient in the enzyme by administration of an inhibitor. They compared these data with plasma... 

Figure 1.30 Catabolic pathway of capecitabine from 19F NMR analysis of patients urine. All the compounds are represented in neutral form. CAP, capecitabine 5 dFCR, 5 -deoxy-5-fluorocytidine FC, 5-fluorocytosine OHFC, hydroxy-5-fluorocytosine 5 dFUR, 5 -deoxy-5-fluorouridine FU, 5-fluorouracil FUH2/ 5,6-dihydro-5-fluorouracil FUPA, a-fluoro-fi-ureidopropionic acid FBAL, u-fluoro-fi-alanine I, fluoride ion FHPA, 2-fluoro-3-hydroxypropanoic acid FAC, fluoroacetic acid. Metabolites identified for the first time in urine of patients with 19F NMR are represented in ellipses.

Several examples of prodrugs are found in the purine and pyrimidine analogs that substitute for natural nucleotides and inhibit nucleic acid formation. For example, 5-fluorouracil is essentially harmless to mammalian host and tumor cells. Upon administration, the drug is subject to one of two opposingmetabolicfates (10). Inactivation and elimination are accomplished by catabolism (about 80% of the dose) and by urinary excretion of unchanged drug... 

Fluorouracil is catabolized in an analogous manner to uracil, forming the following degradative products dihydrofluorouraci1, a-fluoro-6-ureidopropionic acid, a-fluoro-3-guanidopropionic acid, a-fluoro-3-alanine, urea, and CO2 (16). 

Pharmacokinetics The pharmacokinetics of fluorouracil are non-linear and there is marked inter- and intra-patient variability. Oral absorption is erratic, with systemic availability of 40-70%. The primary plasma half-life is 8-14 minutes after a standard bolus dose of 370-720 mg/m but is dose related. As catabolism of fluorouracil by dihydropyrimidine dehydrogenase is saturable, its clearance decreases with higher doses and with bolus doses compared with infusions. 

An alternative activation pathway involves the thymidine phosphorylase catalysed conversion of 1 to Floxuridine (FUDR, 4), which is then phosphorylated by thymidine kinase to give 19. The metabolite of 1 - Floxuridine - is itself used as an anti-cancer agent [9]. It was launched in 1970 by Hospira hic [5]. Upon rapid injection, most of Hoxuiidine is catabolized to Fluorouracil hence similar effects on the organism are obtained in this case. On the contrary, when 4 is slowly administered into the arterial blood, it is mostly transformed to 19 thus toxic effects are diminished comparing to 1 [10]. 

In vivo NMR spectroscopy can be a very useful technique for monitoring the distribution of fluori-nated drugs and their metabolites. These include the PET agent 2-fluoro-2-deoxyglucose, the study of its 3-fluoro-isomer as a probe of aldose reductase activity in brain, the elimination from the brain of fluori-nated anaesthetics, metabolism of halothane in the liver, the distribution and catabolism of the anticancer drug 5-fluorouracil and the uptake of trifluoro-methylthymidine into mouse tumours. 

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