title: Potential pharmacokinetic role of organic cation transporters in modulating the transcorneal penetration of its substrates administered topically.
abstract: OBJECTIVE
  We hypothesize organic cation transporters (OCT) may have a potential role in determining the pharmacokinetics and toxicity of organic cation drugs applied topically. Hence, in the present in vivo study, we attempted to evaluate the role of OCT in modulating the transport of its substrates after topical application.
  
  
  METHODS
  New Zealand albino rabbits of either sex were used. Transcorneal penetration of OCT substrates tetraethylammonium and metformin after single instillation was evaluated in the absence and presence of OCT blockers (quinidine and atropine). Aqueous humor (AH) samples were collected through paracentesis amounting to 70-100 μl under topical anesthesia at various time intervals. The samples were subjected for estimation of both substrate as well as blocker concentrations using liquid chromatography mass spectrometry.
  
  
  RESULTS
  Topical pre-treatment (30 min before substrate) of OCT blockers significantly decreased the transcorneal penetration of OCT substrates after single topical administration. The levels of blockers reaching AH in the presence of substrates were also modulated at 60 min after its administration as compared with its control.
  
  
  CONCLUSIONS
  OCT are functionally active in the uptake of their substrates from tear to AH. Therefore, OCT in the corneal epithelium may be positioned from apical to basolateral. When administering their substrates/blockers topically, both may be competing for OCT for their uptake across the cornea, thereby decreasing the corneal penetration. Hence OCT can have a potential pharmacokinetic role in modulating the ocular bioavailability of their substrates administered topically, which are used as ocular therapeutics.
authors.affiliation: Department of Ocular Pharmacology and Pharmacy, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
authors.forename: J
authors.initials: J
authors.lastname: Nirmal
authors.forename: S B
authors.initials: SB
authors.lastname: Singh
authors.forename: N R
authors.initials: NR
authors.lastname: Biswas
authors.forename: V
authors.initials: V
authors.lastname: Thavaraj
authors.forename: R V
authors.initials: RV
authors.lastname: Azad
authors.forename: T
authors.initials: T
authors.lastname: Velpandian
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001285:Atropine / Q000494:pharmacology; D001692:Biological Transport; D002853:Chromatography, Liquid; D003315:Cornea / Q000378:metabolism*; D013058:Mass Spectrometry; D008687:Metformin / Q000493:pharmacokinetics; D023421:Models, Animal; D027701:Organic Cation Transport Proteins / Q000493:pharmacokinetics*; D011802:Quinidine / Q000494:pharmacology; D011817:Rabbits; D019789:Tetraethylammonium / Q000493:pharmacokinetics*; D041623:Tomography, Optical Coherence; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D027701:Organic Cation Transport Proteins; D061567:Voltage-Gated Sodium Channel Blockers; D019789:Tetraethylammonium; D001285:Atropine; D008687:Metformin; D011802:Quinidine