Metabolic Fate of 1-Hexylcarbamoyl-5-fluorouracil in Rats

Abstract

1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro [6-14C]uracil (14C-HCFU) in rats after oral administration was compared with that of 5-fluoro[6-14C]uracil (14C-FU). 2. Tissue radioactivity reached a max. 1 to 3 h after administration of 14C-HCFU and 0.5 h after 14C-FU. 3. Both drugs were excreted rapidly, mostly in urine. Expired 14CO2 from 14C-HCFU was significantly less than that from 14C-FU. 4. Unchanged FU was not detected in plasma 3 h after administration of 14C-FU, whereas FU was detected in plasma 5 h after 14C-HCFU. The pyrimidine ring of 14C-HCFU might be degradated more slowly than that of 14C-FU. 5. 1-(5-Carboxypentylcarbamoyl)-5-fluorouracil and 1-(3-carboxypropylcarbamoyl)-5-fluorouracil were identified as the major urinary metabolites of 14C-HCFU.

Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity

“…The anticancer properties of carmofur have been attributed to the ability of this agent to generate 5–FU1314242526, a pyrimidine analog that inhibits DNA synthesis in tumor cells by blocking thymidylate synthase27. Nevertheless, the lack of positive correlation between carmofur-induced inhibition of thymidylate synthetase activity and cell proliferation is suggestive of a more complex mechanism of action14.…”

A New Use for an Old Drug: Carmofur Attenuates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Inhibition of FAAH and NAAA Activities

“…Carmofur was eluted by CH 3 CN/H 2 O (50/50, v/v, 0.25% phosphoric acid) with a flow rate of 1.0 ml min −1 at 40°C and determined by UV detection at 260 nm. Carmofur in the lung homogenate with concentrations ranging from 500 to 20,000 ng/ml was prepared for the external standard curve (Kobari et al, 1978).…”

Versatile use of Carmofur: A comprehensive review of its chemistry and pharmacology

“…However, a study using 14 C radioactive carmofur and 5‐FU demonstrated that carmofur was rapidly absorbed and reached highest tissue concentration within 1–3 h of oral administration, whereas it was only 0.5 h for 5‐FU in rats. Equimolar administration of the 14 C‐carmofur and 14 C‐5‐FU indicated that the pyrimidine ring in carmofur degrades slowly and therefore, unchanged 5‐FU was detected for a longer period of time (>5 h) for carmofur than it is for 14 C‐5‐FU (Kobari et al, 1978). Ooi et al (2001) studied the plasma level of 5‐FU after oral administration of carmofur in mice.…”

“…Carmofur has also been observed to cross the blood‐brain barrier and distribute itself in brain compartment which can be attributed to the lipophilic aliphatic tail of the compound, however, to what extent is not well understood (Iigo et al, 1979). About 90% of the drug was found to be excreted through urine within 48 h of administration, some into the air, and a very low amount in the feces (IIGO et al, 1981; Kobari et al, 1978). The peaks for carmofur were observed between 1 and 2 h in human and a half‐life of about 2 h. In addition, the peak concentration for the metabolite 5‐FU appeared at the same time (Ikehira et al, 1999).…”

“…Taken all the structural features together, the authors proposed a new analog 6 (Figure 4) as the most promising analog in terms of molecular interaction against human acid ceramidase homology model (Bhattacherjee & Bhabak, 2016). Dog, mouse, Human, rat, rabbit (Iigo et al, 1980Isomura et al, 1981;Kobari et al, 1978Kobari et al, , 1981Kono et al, 1979) 2 1 -(5′-oxohexylcarbamoyl)-5-fluorouracil OHCFU Serum, plasma, urine, liver, kidney Human, rat, rabbit, dog, mouse (Iigo et al, 1980;Kobari et al, 1981;Kono et al, 1980) 3 1 -(5′-hydroxyhexylcarbamoyl)-5-fluorouracil HHCFU Plasma, serum, urine, liver, lung, kidney Human, rat, rabbit, dog, mouse (Iigo et al, 1980Kobari et al, 1981;Kono et al, 1980) 4 1 -(carboxypentylcarbamoyl)-5-fluorouracil CPEFU Plasma, serum, tumor, urine, liver, kidney Human, rat, rabbit, dog, mouse (Iigo et al, 1980;Kobari et al, 1978Kobari et al, , 1981Kono et al, 1979;Nakajima et al, 1981) 5 1 -(carboxypropylcarbamoyl)-5-fluorouracil CPRFU Plasma, serum, tumor, urine, liver, kidney Human, rat, rabbit, dog, mouse (Iigo et al, 1980Kobari et al, 1978Kobari et al, , 1981Kono et al, 1979;…”