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Pharmacokinetics and tissue distribution of tacrolimus (FK506) after a single or repeated ocular instillation in rabbits.

Authors
  • Fujita, Eriko1
  • Teramura, Yoshinori
  • Shiraga, Toshifumi
  • Yoshioka, Shin-Ichi
  • Iwatsubo, Takafumi
  • Kawamura, Akio
  • Kamimura, Hidetaka
  • 1 Drug Metabolism Research Laboratories, Astellas Pharma Inc., Tokyo, Japan. [email protected] , (Japan)
Type
Published Article
Journal
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics
Publication Date
Jun 01, 2008
Volume
24
Issue
3
Pages
309–319
Identifiers
DOI: 10.1089/jop.2007.0083
PMID: 18476801
Source
Medline
Language
English
License
Unknown

Abstract

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. 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. 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. 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).

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