Intraocular availability of topically applied mycophenolate mofetil in rabbits.
The efficacy of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), in high risk keratoplasties and ocular immune-mediated diseases has been shown in recent years. As peroral administration of MMF can cause various side effects, topical application should be considered. This study investigates the intraocular availability of MMF and MPA in the rabbit eye. An eye drop solution (MMF-CD; 1% MMF/10% hydroxypropyl-beta-cyclodextrin (HP-beta-CD)) or a 1% aqueous suspension (MMF-SP) was instilled into the lower cul-de-sac of the right eye of each rabbit. Rabbits (each group: n = 4) were put down after 30, 60 and 240 min. Aqueous humor, vitreous, cornea, sclera, conjunctiva, iris-ciliary-body, and plasma were isolated. Several extraction procedures were performed in order to quantify the drug by HPLC. The aqueous humor concentration of the active metabolite MPA was 24 microg/mL after 30 min for both preparations. The ratio of the MPA concentrations after 30, 60, and 240 min was 1 : 2 : 0.07 for MMF-CD and 1 : 0.6 : 0.04 for MMF-SP, respectively. MPA levels in the cornea were 90.78 / 56.90 / 4.08 x 10(-6) microg/microg for MMF-CD, whereas MMF-SP resulted in MPA levels of 102.65 / 31.18 / 2.59 x 10(-6) microg/microg at the three time points. As a high concentration of the active drug MPA in cornea and aqueous humor is desired, e.g. following corneal transplantation, the MMF/HP-beta-CD formulation could be an useful topical treatment. Furthermore, the present study shows that MMF-CD is superior to MMF-SP by increasing intraocular availability.
Knapp
Sigrid
S
Institut für Pharmazie, Humboldt Universität zu Berlin, Goethestr. 54, 13086 Berlin, Germany. sigrid.knapp@gmx.de
Bertelmann
Eckart
E
Hartmann
Christian
C
Keipert
Sigrid
S
Pleyer
Uwe
U
D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D005123:Eye / Q000187:drug effects / Q000378:metabolism*; D006868:Hydrolysis; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D009994:Osmolar Concentration; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011817:Rabbits; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D011355:Prodrugs; D009173:Mycophenolic Acid