title: Evaluation of the modulation of P-glycoprotein (P-gp) on the intraocular disposition of its substrate in rabbits.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ocular Pharmacology and Pharmacy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Senthilkumari
authors.forename: Thirumurthy
authors.initials: T
authors.lastname: Velpandian
authors.forename: Nihar Ranjan
authors.initials: NR
authors.lastname: Biswas
authors.forename: Rohit
authors.initials: R
authors.lastname: Saxena
authors.forename: Supriyo
authors.initials: S
authors.lastname: Ghose
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005123:Eye / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007267:Injections; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D017551:Microdialysis; D011817:Rabbits; D012160:Retina / Q000378:metabolism; D020112:Rhodamine 123 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D014018:Tissue Distribution / Q000187:drug effects; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D002352:Carrier Proteins; D005456:Fluorescent Dyes; D044005:Tetrahydroisoquinolines; D020112:Rhodamine 123; C083501:Elacridar; D012293:Rifampin