Pharmacokinetics and tissue distribution of tacrolimus (FK506) after a single or repeated ocular instillation in rabbits.
OBJECTIVE
The aim of this study was to investigate the ocular distribution of tacrolimus (FK506) and absorption into the systemic circulation after a single or repeated topical instillation of FK506 ophthalmic suspension in male New Zealand white rabbits.


METHODS
In the single instillation study (group 1), 29.1-34.8 microL of a 0.1, 0.3, and 1% suspension was administered to each of the 15 rabbits. In the repeated instillation study (group 2), 27.1-39.5 microL of a 0.3% suspension was administered to 27 rabbits q.i.d. (i.e., at 3-h intervals) for 14 days. In the intravenous (i.v.) dose study (group 3), 1 mg/kg of FK506 was administered to 3 rabbits. The amount of FK506 was measured by using a competitive enzyme immunoassay.


RESULTS
The results for single and repeated instillation studies were similar. In the single instillation study, blood T(max) after an instillation of the 0.1, 0.3, and 1% suspensions (at 0.8, 1.0, and 1.0 hours) did not differ significantly among these doses. One (1) h after an instillation of the 1% suspension, ocular tissue concentrations, except the retina/choroid, vitreous body, and lens, were higher than the blood concentration (C(max): 2.7 ng/mL). In particular, concentrations in the conjunctiva, cornea, iris, and anterior sclera were much higher than the blood concentration (148, 900, 120, and 145 ng/g tissue). In the repeated instillation study, concentrations in the blood and ocular tissues (except the lens) reached a steady state by the 7th day. In the i.v. dose study, AUC(0-24h) and T(1/2) were 1643 ng h/mL and 18.5 h, respectively.


CONCLUSIONS
The high-level distribution of FK506 was observed in the conjunctiva, which is desirable because the conjunctiva is the target tissue for pharmacologic effect (i.e., efficacy).
Fujita
Eriko
E
Drug Metabolism Research Laboratories, Astellas Pharma Inc., Tokyo, Japan. eriko.fujita@jp.astellas.com
Teramura
Yoshinori
Y
Shiraga
Toshifumi
T
Yoshioka
Shin-Ichi
S
Iwatsubo
Takafumi
T
Kawamura
Akio
A
Kamimura
Hidetaka
H
D000042:Absorption; D000287:Administration, Topical; D000465:Algorithms; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D009883:Ophthalmic Solutions; D011817:Rabbits; D013535:Suspensions; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D013535:Suspensions; D016559:Tacrolimus