title: Interaction of ocular hypotensive agents (PGF2 alpha analogs-bimatoprost, latanoprost, and travoprost) with MDR efflux pumps on the rabbit cornea.
abstract: OBJECTIVE
  The objectives of this work were (i) to screen ocular hypotensive prostaglandin (PGF2 alpha) analogs--bimatoprost, latanoprost, and travoprost as well as their free acid forms--for interaction with efflux pumps on the cornea and (ii) to assess the modulation of efflux upon co-administration of these prostaglandin analogs.
  
  
  METHODS
  Cultured rabbit primary corneal epithelial cells (rPCEC) were employed as an in vitro model for rabbit cornea. Transporter-specific interaction studies were carried out using Madin-Darby canine kidney (MDCK) cells overexpressing MDR1, MRP1, MRP2, MRP5, and BCRP. Freshly excised rabbit cornea was used as an ex vivo model to determine transcorneal permeability.
  
  
  RESULTS
  Cellular accumulation studies clearly showed that all prostaglandin analogs and their free acid forms are substrates of MRP1, MRP2, and MRP5. Bimatoprost was the only prostaglandin analog in this study to interact with P-gp. In addition, none of these molecules showed any affinity for BCRP. K (i) values of these prostaglandin analogs obtained from dose-dependent inhibition of erythromycin efflux in rPCEC showed bimatoprost (82.54 microM) and travoprost (94.77 microM) to have similar but higher affinity to efflux pumps than latanoprost (163.20 microM). Ex vivo studies showed that the permeation of these molecules across cornea was significantly elevated in the presence of specific efflux modulators. Finally, both in vitro and ex vivo experiments demonstrated that the efflux of these prostaglandin analogs could be modulated by co-administering them together.
  
  
  CONCLUSIONS
  Bimatoprost, latanoprost, travoprost, and their free acid forms are substrates of multiple drug efflux pumps on the cornea. Co-administration of these molecules together is a viable strategy to overcome efflux, which could simultaneously elicit a synergistic pharmacological effect, since these molecules have been shown to activate different receptor population for the reduction of intraocular pressure (IOP).
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64110, USA.
authors.forename: Sudharshan
authors.initials: S
authors.lastname: Hariharan
authors.forename: Mukul
authors.initials: M
authors.lastname: Minocha
authors.forename: Gyan P
authors.initials: GP
authors.lastname: Mishra
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.forename: Rohit
authors.initials: R
authors.lastname: Krishna
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000069580:Bimatoprost; D002460:Cell Line; D003008:Cloprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003315:Cornea / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019573:Epithelium, Corneal / Q000166:cytology / Q000378:metabolism*; D004917:Erythromycin / Q000493:pharmacokinetics; D000077338:Latanoprost; D008297:Male; D010539:Permeability; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage / Q000493:pharmacokinetics; D011817:Rabbits; D000069557:Travoprost
chemical_list: D018528:ATP-Binding Cassette Transporters; D000577:Amides; D000959:Antihypertensive Agents; D011461:Prostaglandins F, Synthetic; D003008:Cloprostenol; D004917:Erythromycin; D000077338:Latanoprost; D000069580:Bimatoprost; D000069557:Travoprost