Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs.
OBJECTIVE
To determine the ocular pharmacokinetics of cyclosporin A after topical ophthalmic administration.


METHODS
Radiolabled cyclosporin A in either a castor oil-in-water emulsion or a corn oil ointment was applied to the eyes of beagle dogs or albino rabbits using the following paradigms: (i) single doses of 0.2% emulsion to rabbits and dogs, (ii) single doses of 0.05%, 0.2%, or 0.4% emulsion to rabbits, (iii) multiple doses of 0.2% emulsion to dogs, (iv) single and multiple doses of 0.2% ointment to rabbits. The distribution of cyclosporin A was determined by measuring the distribution of radioactivity.


RESULTS
After a single dose, cyclosporin A was rapidly absorbed into the conjunctiva (Cmax: dogs, 1490 ng/g; rabbits, 1340 ng/g) and cornea (Cmax: dogs, 311 ng/g; rabbits, 955 ng/g). High concentrations (>300 ng/g) could be detected in the cornea up to 96 hours post-dose. Lower concentrations were found in the intraocular tissues, and systemic absorption was minimal. After multiple doses, there was some accumulation in the cornea, lens, lacrimal gland, and iris-cilliary body, but limited accumulation in the conjunctiva and sclera. Ocular tissue concentrations of cyclosporin A increased with increasing dose concentration; proportionally in lacrimal gland and intraocular tissues; less than proportionally in conjunctiva and cornea. The pharmacokinetic profile of the cyclosporin A corn oil ointment was similar to that of the emulsion.


CONCLUSIONS
Topical ophthalmic cyclosporin A penetrated into extraocular tissues at concentrations adequate for local immunomodulation while penetration into intraocular tissues was much less and absorption into the blood was minimal.
Acheampong
A A
AA
Allergan, Irvine, CA 92715, USA. acheampong_andrew@Allergan.com
Shackleton
M
M
Tang-Liu
D D
DD
Ding
S
S
Stern
M E
ME
Decker
R
R
D000042:Absorption; D000287:Administration, Topical; D000818:Animals; D002924:Ciliary Body / Q000378:metabolism; D003228:Conjunctiva / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004655:Emulsions; D005123:Eye / Q000378:metabolism*; D005260:Female; D007498:Iris / Q000378:metabolism; D007765:Lacrimal Apparatus / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000493:pharmacokinetics; D011817:Rabbits; D012590:Sclera / Q000378:metabolism; D014018:Tissue Distribution
D004655:Emulsions; D009883:Ophthalmic Solutions; D016572:Cyclosporine