5-Fluorouracil prodrug

Okuda H, Nishiyama T, Ogura K et al. Lethal drug interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. DrugMetab Dispos 1997 25 270-273. 

Luo Q, Wang P, Miao Y, He H, Tang X. A novel 5-fluorouracil prodrug using hydroxy-ethyl starch as a macromolecular carrier for sustained release. Carbohydr Polym... 

Uncertain. However, in a pharmacokinetic study in rats, fluorouracil significantly reduced the total clearance of5-warfarin by inhibiting its metabolism. Data from the clinical study with the fluorouracil prodrug, capecitabine, suggests this interacts similarly. ... 

Marked and rapidly fatal toxicity, attributed to fluorouracil toxicity, has been seen in patients given tegafur or other fluorouracil prodrugs with sorivudine. Fluorouracil is expected to interact similarly. 

Sorivudine appears to be converted in the gut into a metabolite (BVU or bromovinyluraeil) that is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the metabolism of fluorouracil (which is derived from tegafiir and other fluorouracil prodrugs). There is some evidence that DPD activity is genetically determined, and that there are poor fluorouracil metabolisers with low DPD activity, who would be expected to be more susceptible to this interaction. ... 

Information appears to be limited to these reports but the interaction appears to be established and of clinical importance. The concurrent use of inhibitors of DPD (such as sorivudine and brivudine) and oral fluorouracil prodrugs such as capecitabine and tegafur is contraindicated. Note that sorivudine was withdrawn from the market following confirmation of this interaction. 

Syntheses of Fluorouracil prodrugs relied on either chemical modification of 1 or direct fluorination of the corresponding pyrimidine derivatives. In particular, Tegafur (3) was obtained from 1 by reaction with 2,3-dihydrofuran [49-54], 2-chloro- [55, 56], 2-alkoxy- [57], 2-acetoxytetrahydrofuran [58, 59, 300], and 4-tri-methylsilyloxybutyraldehyde dimethyl acetal (48) (Scheme 9) [60]. Alternatively, 3 was prepared via fluorination of compound 49 [61] or ester 50 [62],... 

Interest contmues in prodrugs of 5-fluorouracil (5-FU) Doxifluridine (8) was recently mtroduced and appears to be more potent and less toxic than 5 FU [10 Flutamide (9) and nilutamide (/O) are both available for the treatment of prostatic cancer [//, 12]... 

Lethal drug interactions of new antiviral, sorivudin [l-(3-D-arabinofuranosyl-( )-5-(2-bromvinyl)uracil], with anticancer prodrugs of 5-fluorouracil structure 97YZ910. 

Capecitabine (Xeloda ) Orally active prodrug of 5-fluorouracil. Once activated, the mechanism of action is the same. Similar to continuous infusion 5-fluorouracil... 

A Buur, L Trier, C Magnusson, P Artursson. Permeability of 5-fluorouracil and prodrugs in Caco-2 cell monolayers. Int J Pharm 129 223-231, 1996. 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Fig. 6.9. Rationale for the design of peptidic prodrugs (6.15) of 5-fluorouracil (6.17) targeting microbial peptides permeases and peptidases [37]...

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

A. Buur, H. Bundgaard, E. Falch, Prodrugs of 5-Fluorouracil. IV. Hydrolysis Kinetics, Bioactivation and Physicochemical Properties of Various N-Acyloxymethyl Derivatives of 5-Fhiorouracil , Int. J. Pharm. 1985, 24, 43 - 60. 

N-Mannich derivatization has also been documented to improve skin delivery [91][92], In the case of theophylline (11.56) and 5-fluorouracil (11.58), a much improved solubility in water of the various N-Mannich bases examined was observed. To avoid breakdown, however, the prodrugs had to be dissolved in a polar nonaqueous solvent (isopropyl myristate) for pharmaceutical use. The delivery of theophylline and 5-fluorouracil through hairless mouse skin was, thus, accelerated approximately sixfold through use of the prodrugs 11.57 and 11.59, respectively. 

M. Malet-Martino, P. Jolimaitre, R. Martino, The prodrugs of 5-fluorouracil, Curr. Med. Chem. Anticancer agents 2 (2002) 267-310. 

The fluorine atom can be present in position 5 in uracil derivatives, or in position 1 in that of purine, as in fludarabine, which is used in the treatment of some leukemias (Figure 6.14 cf. Chapter 8). Nucleoside derivatives of fluorouracil (e.g., capecitabine) are prodrugs that allow the oral administration of 5-FU in cancer chemotherapy. The mechanism of action of these nucleosides is detailed in Chapters 7 and 8. Nucleosides having a trifluoromethylated base have been described for example, trifluridine is active on herpesvirus (Figure 6.14). 

It was previously thought that 5-FU inhibits the enzyme by classical competitive inhibition. However, it was found that 5-FU is a transition-state substrate, and it forms a covalent complex with tetrahydrofolate and the enzyme in the same way that the natural substrate does. The reaction, however, will not go to completion, since the fluoro-uridine derived from the antimetabolite remains attached to the enzyme, and the latter becomes irreversibly deactivated. Recovery can occur only through the synthesis of new enzyme. Fluorouracil is used in the treatment of breast cancer and has found limited use in some intestinal carcinomas. Unfortunately, this drug has the side effects usually associated with antimetabolites. Its prodrug, fluorocytosine (8.35, which is also an antifungal agent) is better tolerated. 

This field was recently reviewed [172]. Enzymes that have been used for ADEPT are, e.g., alkaline phosphatase, carboxypeptidase A, cytosine deaminase, -lactamase prodrugs and corresponding drugs were, e.g., adriamycin phosphate and adriamycin, methotrexate-alanine and methotrexate, 5-fluorocytosine and 5-fluorouracil, and vinca-cephalosporin and vinca alkaloid [172 and references therein]. 

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