Absorption, distribution, and excretion of 14C-labeled tacrolimus (FK506) after a single or repeated ocular instillation in rabbits.
OBJECTIVE
The aim of this study was to investigate the absorption, distribution, and excretion of radioactivity in male rabbits after a single or repeated instillation of (14)C-labeled tacrolimus (FK506) ophthalmic suspension or an intravenous (i.v.) administration of (14)C-FK506.


METHODS
The 0.3% (14)C-FK506 suspension was administered in single and repeated (three times, 5-min intervals) instillation studies, and 1 mg/kg of (14)C-FK506 was administered in the i.v. dose study.


RESULTS
Results for single and repeated instillation studies were similar. In eyeball microautoradiograms, 15 min after dosing, the level of radioactivity in the cornea was the highest, followed by conjunctiva. After 1 h, little specific distribution was detected in the corneal epithelium, stroma, or Descemet's membrane. At 24 h, the level of radioactivity in the cornea decreased. Whole-body autoradiograms showed that the radioactivity was distributed to the digestive tract through the nasal meatus and esophagus and then was excreted into the feces. In the i.v. dose study, the distribution of radioactivity in whole-body autoradiographs was similar to that in quantitative tissue distribution measurements. The excretion of radioactivity in the urine and feces up to 168 h were 4.5 and 94.9%, respectively.


CONCLUSIONS
After the ocular instillation, FK506 is first absorbed in the cornea, conjunctiva, and nasolacrimal duct, and then the rest is distributed to digestive tract through the nasal meatus and esophagus, after which it is excreted mainly into the feces.
Fujita
Eriko
E
Drug Metabolism Research Laboratories, Astellas Pharma Inc., Tokyo, Japan. eriko.fujita@jp.astellas.com
Teramura
Yoshinori
Y
Mitsugi
Koichi
K
Ninomiya
Shin-Ichi
S
Iwatsubo
Takafumi
T
Kawamura
Akio
A
Kamimura
Hidetaka
H
D000042:Absorption; D000818:Animals; D001345:Autoradiography; D005123:Eye / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000652:urine; D007275:Injections, Intravenous; D008297:Male; D009883:Ophthalmic Solutions; D011817:Rabbits; D013535:Suspensions; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D013535:Suspensions; D016559:Tacrolimus