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Metabolism and Biochemistry of Mycophenolic Acid

The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46206

Mycophenolic acid is a new, experimental oncolytic agent that interferes in the interconversion of inosine, xanthosine, and guanosine monophosphates. IMP dehydrogenase, which converts IMP XMP, and GMP synthetase, which converts XMP GMP, are inhibited by mycophenolic acid. The IMP dehydrogenase from a human adenocarcinoma of the colon was more sensitive to mycophenolic acid than was the enzyme from murine tumors.

There is a correlation between the sensitivity of experimental tumors to mycophenolic acid and the relative activities of ß-glucuronidase and hypoxanthine-guanine phosphoribosyltransferase. Mycophenolic acid glucuronide is unable to cross the cell membrane; therefore the intracellular concentration of the free acid depends on the rate of hydrolysis of the glucuronide by ß-glucuronidase. A mechanism of resistance to mycophenolic acid is the circumvention of the block in the nucleotide interconversion. GMP is resupplied by conversion of guanine to its nucleotide by hypoxanthine-guanine phosphoribosyltransferase. In tumors resistant to mycophenolic acid, the transferase activity is high; in tumors sensitive to mycophenolic acid, the activity is low. The relative activities of these two enzymes in tumors in man may indicate the potential effectiveness of mycophenolic acid in humans.

Mycophenolic acid is initially secreted into the bile and excreted in the urine and feces of animals. ¹⁴CO₂ was not detected in the expired air of mice, rats, or marmosets given ¹⁴C-labeled mycophenolic acid. The only metabolite detected in mice, rats, rabbits, and humans was mycophenolic acid glucuronide.

Received 9/28/71. Accepted 5/ 9/72.

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