Effect of Coadministration of Uracil on the Toxicity of Tegafur

Yamamoto, Jyunji; Haruno, Akihiro; Yoshimura, Yuji; Unemi, Norio; Kunimune, Yoshio; Yamashita, Kazumasa; Morita, Kenichi

doi:10.1002/jps.2600730217

Cited by 17 publications

(10 citation statements)

References 12 publications

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“…26,27 Because the patterns of toxicity development clearly differ between DIF preparations and non-DIF preprations, 28-31 the possibility cannot be denied that control or inhibition of DPD decreases the degradation products and decreases toxicity. [32][33][34][35] Relation between DPD and sensitivity to 5-FU It is well known that thymidylate synthase (TS), a target enzyme of 5-FU, affects the sensitivity of 5-FU. [36][37][38] It is also reported that DPD determines 5-FU sensitivity.…”

Section: Toxicity Caused By 5-fu Catabolitesmentioning

confidence: 99%

5-Fluorouracil and dihydropyrimidine dehydrogenase

Kubota

2003

International Journal of Clinical Oncology

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Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme of (fluorinated) pyrimidine degradation that plays a significant role in the pharmacokinetics of 5-fluorouracil (5-FU). In addition, a catabolite of 5-FU induces a certain toxicity, and the sensitivity of 5-FU is determined by DPD activity in tumors. DPD is thus important clinically. Drugs have been developed that control variations of the pharmacokinetics of 5-FU by controlling or inhibiting DPD, thereby reducing toxicity and improving sensitivity. These fluorinated pyrimidines with DPD-inhibiting activity, called DPD-inhibitory fluoropyrimidines, contribute to oral therapy with 5-FU for cancer. This paper summarizes the important role of DPD in cancer chemotherapy with 5-FU.

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Section: Toxicity Caused By 5-fu Catabolitesmentioning

confidence: 99%

5-Fluorouracil and dihydropyrimidine dehydrogenase

Kubota

2003

International Journal of Clinical Oncology

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“…and Koenig and Patel (1970) reported a similarity between the neuronal disorder produced by 5-fluorouracil (5-FU) and that caused by α-fluoro-β-alanine (FBAL) in cats, and they suggested that 5-FU might to be degraded to fluoro-acetic acid (FA) and then metabolically converted to fluorocitrate (FC). Yamashita et al (1980Yamashita et al ( ,1988 reported that dogs treated orally with a Tegafur (FT-207) and uracil mixture (UFT), Tegafur or 5-FU showed neurotoxic signs and vacuolar changes in the cerebrum, and Yamashita et al (1980and Yamashita et al ( , 1988 and Yamamoto et al (1984) also suggested that the toxic effects of UFT may be caused by its catabolic metabolites such as 5-FU, FBAL, and so on.…”

Section: Introductionmentioning

confidence: 99%

Neurotoxic Effects of .Alpha.-Fluoro-.Beta.-Alanine (Fbal) and Fluoroacetic Acid (Fa) on Dogs

Yamashita

Yada

2004

J. Toxicol. Sci.

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In order to clarify the mechanism of the neurotoxicity of 5-FU and/or its masked compounds, we studied the effects of alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA) on the formation of vacuolar changes in the dog cerebrum, using the dosage of 3.0 mg/kg/day of FBAL-HCl (FBAL x HCl) and 0.03 mg/kg/day of FA-Na (FA x Na), respectively. These 2 compounds were selected because they are the metabolites of 5-FU claimed to be responsible for the neurotoxic effects of 5-FU and/or its masked compounds, and we wanted to confirm their effects. Tegafur-uracil mixture (UFT) was used as a positive control drug for the formation of vacuolar changes in the dog cerebrum. All compounds were orally administered daily for 3 months to beagle dogs. Each study group consisted of 3 males. Neurotoxic signs such as hyperesthesia and/or excitement, as well as convulsions, were observed in both FBAL x HCl and FA x Na groups; these toxic signs were also found in the UFT group. Slight loss of body weight gain and of food consumption was observed in the FBAL x HCl and UFT groups. Neuropathologically, vacuolar changes were detected in several areas of the dog cerebrum following administration of FBAL x HCl, FA x Na or UFT. In terms of morphology, the neuropathological effects of these 2 drugs were very similar to those induced by UFT. In conclusion, we clearly showed that FBAL is one of the main substances that cause neurotoxic signs and neuropathological changes in dogs intoxicated by 5-FU or its masked compounds. Moreover, FA might be considered to be a causative factor in addition to FBAL.

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“…Combination of Tegafur with the uracil (1:4 molar ratio; commonly known as UFT) (DPD inhibitor) has been developed as one of the useful combination for achieving higher tumor and blood levels [87] of 5-FU and reduction in toxicity especially, CNS toxicity, which is mediated by the degradation of 5-FU to α-fluoro-b-alanine by DPD [88]. UFT was also combined with leucovorin (LV) (folinic acid), a metabolism modulator, to further enhance the anticancer activity of Tegafur.…”

Section: Ftorafur ® (Tegafur) and Combination With Dpd Inhibitorsmentioning

confidence: 99%

Advances in oral delivery of anti-cancer prodrugs

Jain

2016

Expert Opinion on Drug Delivery

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Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route. Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed. Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.

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Effect of Coadministration of Uracil on the Toxicity of Tegafur

Cited by 17 publications

References 12 publications

5-Fluorouracil and dihydropyrimidine dehydrogenase

5-Fluorouracil and dihydropyrimidine dehydrogenase

Neurotoxic Effects of .Alpha.-Fluoro-.Beta.-Alanine (Fbal) and Fluoroacetic Acid (Fa) on Dogs

Advances in oral delivery of anti-cancer prodrugs

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