Cytosolic and microsomal activation of doxifluridine and tegafur to produce 5-fluorouracil in human liver.

The enzymatic formation of 5-fluorouracil (5-FU) from two fluoropyrimidine prodrugs, doxifluridine (5'-DFUR) and tegafur (FT), was compared in vitro in order to determine whether there are differences between the metabolic profiles of the two prodrugs. Conversion of the two fluoropyrimidine prodrugs to 5-FU was measured by high-performance liquid chromatography at a concentration of 500 micro M using the microsomal and cytosolic fractions of 12 human livers. The degree of correlation between the 5-FU-forming activities was determined using various cytochrome P450-dependent reactions. Liver microsomes catalyzed 5-FU formation from 5'-DFUR at rates of 10.0-160.1 pmol/min per mg protein and correlated well with CYP2A6-dependent coumarin 7-hydroxylase activity. The rates of microsomal 5-FU formation from FT ranged from 44.9 to 808.3 pmol/min per mg protein and also correlated with coumarin 7-hydroxylase activity. The cytosol fractions catalyzed 5-FU formation from 5'-DFUR at rates of 3,164.6 to 6,026.6 pmol/min per mg protein, almost two orders of magnitude higher than the rates of cytosolic 5-FU formation from FT (46.8-219.0 pmol/min per mg protein). The cytosolic enzymes in livers appear to be important for 5-FU formation from 5'-DFUR. Both cytosolic and microsomal enzymes were involved almost equally in 5-FU formation from FT. The increased formation of 5-FU from 5'-DFUR might provide an answer to the question of why similar blood 5-FU levels were retained despite blood 5'-DFUR levels lower than blood FT levels.

Citation

Shogo Ozawa, Masashi Hamada, Norie Murayama, Yukiko Nakajima, Nahoko Kaniwa, Yoshiaki Matsumoto, Masamichi Fukuoka, Jun-ichi Sawada, Yasuo Ohno. Cytosolic and microsomal activation of doxifluridine and tegafur to produce 5-fluorouracil in human liver. Cancer chemotherapy and pharmacology. 2002 Dec;50(6):454-8

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PMID: 12451471

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