September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Pharmacological investigations of angiotensin II type 1 receptor antagonists reveal effective physiological concentrations in the eye after administration via drinking water
Author Affiliations & Notes
  • Ralph J Hazlewood
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • George Naratadam
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Sayan Paria
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • John Kuchtey
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Rachel W Kuchtey
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Ralph Hazlewood, None; George Naratadam, None; Sayan Paria, None; John Kuchtey, None; Rachel Kuchtey, None
  • Footnotes
    Support  American Glaucoma Society Clinician Scientist Award (RWK); Career Development Award (RWK) and Unrestricted Grant to the Vanderbilt University Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness; Faculty grant from the Marfan Foundation; NIH grants R01EY020894 (RWK), P30EY008126, and 2T32EY007135-21 (RJH)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 1189. doi:
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    • Get Citation

      Ralph J Hazlewood, George Naratadam, Sayan Paria, John Kuchtey, Rachel W Kuchtey; Pharmacological investigations of angiotensin II type 1 receptor antagonists reveal effective physiological concentrations in the eye after administration via drinking water. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1189.

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

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Abstract

Purpose : Angiotensin II type 1 receptor antagonists (sartans) lower intraocular pressure (IOP) in humans and have neuroprotective effects in glaucoma models, and therefore may be effective treatments for glaucoma. Currently, there are eight sartans in clinical use, each with different lipid solubility profiles and active metabolites. The purpose of this study is to investigate the pharmacology of sartans in mouse models as potential treatments for glaucoma.

Methods : Solubility and stability of sartans were determined in different solvents. Losartan was administered to 3 month-old C57BL/6 mice via drinking water. After 1, 3, 7 and 21 days of drug administration, IOP was measured by rebound tonometry and plasma and eyes were harvested. Peak and trough concentrations of losartan and its active metabolite, EXP3174, in plasma and eyes were determined by liquid chromatography/mass spectrophotometry (LC/MS).

Results : All sartans were soluble in 0.1% DMSO/water, whereas only losartan is soluble in water. Recovery of losartan after 9 days at room temperature was ~100%. Recoveries of ~ 80% were achieved for all sartans in 0.1% DMSO/water except for olmesartan and eprosartan, which had low recoveries. Administration of losartan via drinking water resulted in stable concentrations of losartan and its active metabolite of > 30 nM in the whole eye and plasma. Eye and plasma concentrations were not significantly different (p = 0.3). IOP was unaffected by losartan administration (p= 0.6).

Conclusions : Sartans are stable and remain soluble for up to 9 days at RT in 0.1% DMSO, well below the highest allowable dosage to prevent DMSO toxicity, allowing for administration of the drugs via drinking water. Drinking water administration of losartan results in stable physiologically relevant systemic and ocular concentrations of the drug and its active metabolite. IOP of wild type C57BL/6 mice is not affected by losartan. Together these data highlight the importance of further examination of sartans as a potential treatment for glaucoma.

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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