Evaluation of the modulation of P-glycoprotein (P-gp) on the intraocular disposition of its substrate in rabbits

Curr Eye Res. 2008 Apr;33(4):333-43. doi: 10.1080/02713680802015720.

Abstract

Purpose: To evaluate the functional role of P-gp and ocular tissue distribution of intravitreally injected Rhodamine-123 (Rho-123) in the presence of P-gp specific blocker (GF 120918) in normal as well as rifampicin-fed rabbits using microdialysis and direct sampling technique.

Methods: Intravitreal pharmacokinetics of Rho-123 were conducted in male New Zealand albino rabbits. Direct sampling and microdialysis were employed to study the disposition of Rho-123 in normal as well as rifampicin-fed conditions. Control animals received Rho-123 at the concentration of 350 ng in PBS (0.05 ml) intravitreally, and the blocker-treated group received GF 120918 intravenously at the dose of 3.5 mg/kg 30 min prior to intravitreal injection of Rho-123. In case of direct sampling, four eyes were enucleated at different time points, and ocular tissues and humors were stored at -86 degrees C until analysis by HPLC with fluorescence detection.

Results: In direct sampling, the blocker group showed significant increase (2.6 fold) in the mean vitreous concentration of Rho-123. Other tissues like ret-choroid, iris, and cornea also showed significant increase in their mean concentration. Microdialysis did not significantly predict the changes observed with direct sampling. Rifampicin-fed rabbits showed a vitreous pharmacokinetic profile comparable with non-fed (control) animals, and the pharmacokinetic parameters were unaffected by the blocker pretreatment.

Conclusion: Intravenously injected blocker significantly altered the ocular disposition of intravitreally injected P-gp substrate. Rifampicin pretreatment did not upregulate P-gp transporters of the retina to the extent to affect the intravitreal kinetics of Rho-123 significantly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Acridines / administration & dosage
  • Acridines / pharmacology*
  • Animals
  • Blood-Brain Barrier / metabolism
  • Carrier Proteins / metabolism
  • Chromatography, High Pressure Liquid
  • Eye / metabolism*
  • Fluorescent Dyes / administration & dosage
  • Fluorescent Dyes / pharmacokinetics*
  • Injections
  • Injections, Intravenous
  • Kinetics
  • Male
  • Microdialysis
  • Rabbits
  • Retina / metabolism
  • Rhodamine 123 / administration & dosage
  • Rhodamine 123 / pharmacokinetics*
  • Rifampin / pharmacology*
  • Tetrahydroisoquinolines / administration & dosage
  • Tetrahydroisoquinolines / pharmacology*
  • Tissue Distribution / drug effects
  • Vitreous Body / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acridines
  • Carrier Proteins
  • Fluorescent Dyes
  • Tetrahydroisoquinolines
  • Rhodamine 123
  • Elacridar
  • Rifampin