Metabolic fate of ethyl O-(N-(p-carboxyphenyl)-carbamoyl) mycophenolate (CAM), a new antitumor agent, in experimental animals.

Abstract

Absorption, distribution, metabolism and excretion of ethyl O-[N-(p-carboxyphenyl)carbamoyl] mycophenolate (CAM), a new antitumor agent, was studied in mice using 14C-labeled CAM and species difference of metabolism was studied in mice, rats, guinea pigs, rabbits and dogs. CAM was rapidly absorbed from the gastrointestinal tract of mice. Concentration of radioactivity in the plasma of mice showed 2 peaks reflecting enterohepatic circulation of metabolites, the 1st was 30 min and the 2nd was 6 h after dosing. Extremely high concentration of radioactivity was observed in the bile as about 100 times of the radioactivity detected in the plasma. Wide distribution of radioactivity was observed in the whole body tissues of the tumor-bearing mice. Strong radioactivity was presented in the liver, kidney, bile and gastrointestinal content. Radioactivity in the tumor was higher than those in the liver and kidney 24 h after dosing. About 45% of the dose and 30% of the dose were excreted in the urine and feces, respectively, during 24 h after administration of 14C-CAM to mice. The metabolites of CAM were only mycophenolic acid (MPA) and its glucuronic acid conjugate (MPA-G) in all tested animals. Converting ratio of MPA to MPA-G differed greatly among animal species. In the plasma of rats and mice, MPA was presented as higher level than MPA-G at all times. While, in the plasma of rabbits, MPA-G was presented exclusively and MPA was observed only slightly.