September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Possible role of equilibrative nucleoside transporters in the trans-corneal penetration of its substrate cytarabine
Author Affiliations & Notes
  • Hanuman Prasad Sharma
    Ocular Pharmacology & Pharmacy, AIIMS, New Delhi, Delhi, India
  • Baskar Singh
    Department of Biophysics, AIIMS, New Delhi, India
  • Nabanita Halder
    Ocular Pharmacology & Pharmacy, AIIMS, New Delhi, Delhi, India
  • Thirumurthy Velpandian
    Ocular Pharmacology & Pharmacy, AIIMS, New Delhi, Delhi, India
  • Footnotes
    Commercial Relationships   Hanuman Prasad Sharma, None; Baskar Singh, None; Nabanita Halder, None; Thirumurthy Velpandian, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5732. doi:
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      Hanuman Prasad Sharma, Baskar Singh, Nabanita Halder, Thirumurthy Velpandian; Possible role of equilibrative nucleoside transporters in the trans-corneal penetration of its substrate cytarabine. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5732.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Nucleoside transporters help in the transportation of endogenous nucleoside as well as anticancer and antiviral nucleoside drugs at cellular level. The current study was designed to evaluate presence and functional importance of equilibrative nucleoside transporters on cornea.

Methods : PCR analysis of cornea, retina-choroid and iris was done for the identification of nucleoside transporters in rabbits. Trans-corneal penetration studies using topical cytarabine and dipyridamole as suitable substrate and blocker respectively were done on New Zealand Albino rabbits. In two separate studies rabbits were divided into two groups viz. blocker pre-treated and non-blocker. Blocker pretreated group received 20 µl of 2mg/ml dipyridamole 30 min prior to cytarabine for both studies. In first study cytarabine was instilled into the cul-de-sac in a volume of 20 µl (0.2 mg/ml). Aqueous humor was aspirated at 0.5, 1 and 2 hr (n=4; each time point) after cytarabine instillation. In second study cytarabine 0.4, 0.6, 0.8, 1, 5 and 20mg/ml (n=4; each concentration) was instilled in a volume 20 µl in cul-de-sac. Aqueous humor was aspirated at 1 hr after cytarabine instillation. Collected samples were stored at -80 °C till LC-MS/MS analysis.

Results : PCR analysis confirmed the presence of nucleoside transporters at ocular tissues. A sensitive LC-MS/MS method was designed which was capable to separate endogenous cytidine from Cytarabine. In first study, cytarabine attained Cmax at 1 hr and showed a statistically significant difference (p=0.029) between non-blocker and blocker pre-treated groups. AUC(0-2) of non-blocker group was significantly 6 times high compared to blocker pre-treated group (p=0.02). In second study 0.4 and 0.6 mg/ml non-blocker groups showed significantly higher substrate values (p=0.02). No significant difference was found between non-blocker and blocker pre-treated groups for 0.8, 1, 5 and 20mg/ml cytarabine.

Conclusions : Expression analysis and trans-corneal penetration studies indicate role of equilibrative nucleoside transporters in the disposition of cytarabine. Dipyridamole acts as a competitive blocker for the cytarabine and further indicate its utility in nucleoside transporter studies. Further studies using other substrates are in progress to prove the availability of other subtypes of equilibrative nucleoside transporters.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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