Mycophenolic acid is effective against a wide range of experimental
tumors in rodents when given orally, despite rapid metabolism to the inactive
glucuronide derivative and rapid clearance from plasma. In the light of this, the pharmacodynamic action of
mycophenolic acid on the radiolabelling of
GTP and
ATP by [14C]
hypoxanthine in spleen and heart has been investigated in vivo in the rat as a preliminary to studies in
tumor tissue. The data indicate that inhibition of
GTP, and more surprisingly,
ATP synthesis in spleen was sustained for at least 24.25 hr after single oral doses of the disodium
salt of
mycophenolic acid, indicating that the inhibitor is retained in sensitive cells for considerably longer than might be expected from the pharmacokinetic profile in the plasma in this species.
GTP and
ATP levels became depressed in rat spleen subsequent to the inhibition of
nucleotide radiolabelling. The persistence of
mycophenolic acid in proliferating cells may account for the effectiveness of once daily dosing against rapidly growing experimental
tumors. In contrast with spleen, there was no incorporation of radiolabel from [14C]
hypoxanthine into either
GTP or
ATP in rat heart and
mycophenolic acid had no effect on the cardiac content of either
nucleotide. The lack of effect of
mycophenolic acid on cardiac
GTP levels is consistent with the absence of any pharmacological action on cardiac functions associated with receptor-
G-protein-
GTP interactions. The ability of the morpholinoethyl
ester of
mycophenolic acid (a clinically effective
immunosuppressive agent) to inhibit
GTP synthesis and depress
GTP levels in rat spleen in vivo was compared with that of mycophenolic free
acid and its disodium
salt. The
ester derivative was clearly more effective than the poorly water-soluble free
acid but showed comparable activity with the freely soluble disodium
salt.