Pharmacokinetics and Tissue Distribution of Tacrolimus (FK506) After a Single or Repeated Ocular Instillation in Rabbits

J Ocul Pharmacol Ther. 2008 Jun;24(3):309-19. doi: 10.1089/jop.2007.0083.

Abstract

Purpose: 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).

Publication types

  • Comparative Study

MeSH terms

  • Absorption
  • Administration, Topical
  • Algorithms
  • Animals
  • Dose-Response Relationship, Drug
  • Eye / metabolism*
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / pharmacokinetics*
  • Injections, Intravenous
  • Male
  • Ophthalmic Solutions
  • Rabbits
  • Suspensions
  • Tacrolimus / administration & dosage*
  • Tacrolimus / pharmacokinetics*
  • Tissue Distribution

Substances

  • Immunosuppressive Agents
  • Ophthalmic Solutions
  • Suspensions
  • Tacrolimus