April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
RE-AFFIRMATION OF THE IMPORTANCE OF EXTENSIVE BIODISPOSITION DATA FOR RELIABLE INTERPRETATION OF OCULAR DRUG EFFECTS
Author Affiliations & Notes
  • David F Woodward
    Biol Sci RD-2C, Allergan, Inc, Irvine, CA
  • Jenny W Wang
    Biol Sci RD-2C, Allergan, Inc, Irvine, CA
  • Elaine H Tang
    Biol Sci RD-2C, Allergan, Inc, Irvine, CA
  • Carol B Toris
    Dept. of Ophthalmology, University of Nebraska Medical Center, Omaha, NE
  • Footnotes
    Commercial Relationships David Woodward, Allergan Inc. (E); Jenny Wang, Allergan Inc (E); Elaine Tang, Allergan Inc. (E); Carol Toris, Allergan Inc. (F)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 5248. doi:
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      David F Woodward, Jenny W Wang, Elaine H Tang, Carol B Toris; RE-AFFIRMATION OF THE IMPORTANCE OF EXTENSIVE BIODISPOSITION DATA FOR RELIABLE INTERPRETATION OF OCULAR DRUG EFFECTS. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5248.

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

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Abstract

Purpose: A previous comprehensive analysis of prostanoid receptor antagonist effects on monkey intraocular pressure (IOP) showed no activity, despite agonist induced ocular hypotension. The absence of antagonist responses was further investigated by ocular biodisposition studies.

Methods: Ocular drug biodispositions were determined in New Zealand rabbits at 1, 2, 4, 8 and 24 hours post-topical dosing with one animal assigned to each time point . Antagonists dosed at 1% were SC-51322 (EP1), PF-04418948 (EP2), L-826266 (EP3), GW-627368 (EP4), BW-A868C (DP1), AS- 604872 (FP), RO-3244019 (IP). Analyses were by LC/MS/MS.

Results: Marked differences in ocular anterior segment biodisposition were apparent among the antagonists. Despite the high doses employed (1%), the EP1 (SC-51322) and the EP3 (L-826266) antagonists were essentially absent from the aqueous humor and iris/ciliary body. All antagonists, were still present at 24 hours post-dosing, except for the DP1 antagonist BW-A868C , SC-51322 and L-826266 The FP antagonist (AS-604872) preferentially accumulated in the palpebral conjunctiva to an extent where any effects on endogenous PGF present in the outflow pathways could be difficult to block with the concentrations of AS-604872 achieved in the ciliary body and aqueous humor. Considering the bioavailability and potencies of the antagonists at EP2 (PF-04418948), EP4 (GW-627368 ), and IP (RO-3244019) receptors, it could be confidently concluded that these receptors play no significant role in regulating IOP. There are implications beyond studying IOP , SC-51322 and L-826266 levels were relatively low and transient in the cornea .

Conclusions: Of the seven prostanoid receptors antagonists studied, only PF-04418948 , GW626368 , and RO-3244019 provided sufficient ocular bioavailability to draw a reliable inference that endogenously expressed EP2 , EP4 , and IP receptors do not regulate IOP . The palpebral conjunctiva provides a potential tissue site for enormous drug deposition/sequestration. This study re-affirms the need for comprehensive ocular biodistribution pre-determination before pharmacological evaluations .

Keywords: 506 eicosanoids • 675 receptors: pharmacology/physiology • 455 ciliary body  
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