title: Intravenous infusion of RMP-7 increases ocular uptake of ganciclovir.
abstract: OBJECTIVE
  The ability of intravenous (i.v.) infusions of the bradykinin agonist, RMP-7, to permeabilize the blood-ocular barriers (BOB) to the antiviral agent ganciclovir was investigated in guinea-pigs.
  
  
  METHODS
  Different i.v. dosing regimens included pre-treatment with RMP-7 (0.2 microg/kg/min for 5 min) followed by either [3H]-ganciclovir (1 microCi/0.2 ml/min) alone, and/or co-infusion with RMP-7 and [3H]-ganciclovir. At specific times the animals were sacrificed, their eyes removed, and the retina and lens epithelium dissected and analyzed for the amount of radioactivity.
  
  
  RESULTS
  Using the ratio of tissue vs. integrated plasma radioactivity concentration, a two-fold increase in ganciclovir steady-state levels were observed in the retina as well as lens epithelium following RMP-7 pretreatment. Peak uptake effects were achieved with a 4.5 min ganciclovir infusion. Neither longer infusions of ganciclovir alone, nor co-infusions of RMP-7 and ganciclovir further enhanced the uptake effects. Kinetic analysis indicated that RMP-7 increased the rate of ganciclovir entry (K(IN)) in studied ocular tissues, while the efflux of drug (K(OUT)) was not affected by this treatment. Finally, ganciclovir retina:plasma ratios elevated by RMP-7 pre-treatment, remained higher than control ratios within 60 min following cessation of 4.5 min ganciclovir infusion.
  
  
  CONCLUSIONS
  These data offer further evidence that BOB and in particular the blood-retinal barrier can be permeabilized via bradykinin receptor stimulation. As the i.v. infusions of RMP-7 enhanced the retinal uptake of ganciclovir, it is suggested that a combination of RMP-7 and ganciclovir may provide a novel approach for treating cytomegalovirus retinis.
authors.affiliation: Alkermes Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Elliot
authors.forename: R T
authors.initials: RT
authors.lastname: Bartus
authors.forename: J B
authors.initials: JB
authors.lastname: Mackic
authors.forename: B V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D018916:Blood-Aqueous Barrier / Q000187:drug effects; D001813:Blood-Retinal Barrier / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015774:Ganciclovir / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D007262:Infusions, Intravenous; D007908:Lens, Crystalline / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D012160:Retina / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C089876:RMP 7; D015774:Ganciclovir; D001920:Bradykinin