Pharmacodynamics of the inhibition of GTP synthesis in vivo by mycophenolic acid.
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.
Franklin
T J
TJ
Department of Cancer Research, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, U.K.
Morris
W P
WP
D000255:Adenosine Triphosphate / Q000032:analysis; D000284:Administration, Oral; D000818:Animals; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D005260:Female; D006160:Guanosine Triphosphate / Q000096:biosynthesis*; D007168:IMP Dehydrogenase / Q000187:drug effects*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000378:metabolism
D004304:Dosage Forms; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid