Stability and pharmacokinetic studies of a new immunosuppressant, mycophenolate mofetil (RS-61443), in rats.
Mycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The enzymatic and non-enzymatic hydrolysis was studied in an artificial digestive fluid, rat plasma, and tissue homogenates. MPM was chemically stable in the artificial digestive fluid. In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA. The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver > kidney > plasma > small-intestine epithelial cells. After the intravenous injection of MPM at 16.7 mg kg-1, the terminal elimination half-life, t1/2 beta, was 4.74 +/- 0.33 (mean +/- SD)h, and the area under the plasma concentration versus time curve, AUC, was 48.78 +/- 6.01 micrograms h mL-1. After intraduodenal (ID) administration of MPM at 16.7 mg kg-1, t1/2 beta was 3.92 +/- 1.05 h, and the AUC was 38.08 +/- 8.30 micrograms h mL-1. The systemic availability of MPA after ID MPM dosing was 1.52 times higher than that after ID administration of MPA. This result supports the usefulness of MPM as an oral prodrug of MPA as a new oral immunosuppressant.
Sugioka
N
N
Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Japan.
Chen
S H
SH
Hayashida
K
K
Koyama
H
H
Ohta
T
T
Kishimoto
H
H
Yasumura
T
T
Takada
K
K
D000818:Animals; D004355:Drug Stability; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010599:Pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid