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Ocular Pharmacokinetics and Pharmacodynamics of Synthetic Cannabinoid, O‐1812, in a Perfused Rat Eye Model
Author(s) -
Samudre Sandeep,
Lattanzio Frank A,
Martin Billy R,
Castillo Ivan,
Hosseini Alireza,
Frazier Mauro,
Williams Patricia B
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a417-c
Subject(s) - microdialysis , intraocular pressure , pharmacokinetics , glaucoma , in vivo , pharmacology , intravitreal administration , pharmacodynamics , cannabinoid , medicine , ocular hypertension , electroretinography , chemistry , anesthesia , ophthalmology , retinal , endocrinology , central nervous system , receptor , biology , microbiology and biotechnology
Sequential pharmacokinetic (PK) and pharmacodynamic (PD) studies in ocular compartments are limited by the amount of sample that can be obtained. Microdialysis was employed to circumvent this problem. Ocular penetration and disposition of topically applied O‐1812, a synthetic, lipid soluble cannabinoid agonist, were measured by HPLC using microdialysis samples from anterior (AC) and posterior (PC) chambers in the in situ perfused rat eye. Concentrations obtained were compared to effects of O‐1812 on intraocular pressure (IOP), heart rate (HR) and blood pressure (BP) in a rat glaucoma model. Neuroprotective effects of O‐1812 were evaluated in a rat NMDA model by electroretinogram (ERG). A single topical dose of O‐1812 (24 mM) was administered. After 30 min, 6.7 nM O‐1812 present in the AC corresponded to an IOP reduction of 30 ± 0.9 % in the glaucoma model ( p<0.01 ). After 120 min, AC concentration was 4.3 nM with IOP reduction of 40 ± 0.5 %. No systemic effects on HR or BP were noted. The PC concentration was 2.2 nM at 30 min and 1.6 nM at 120 min; in vivo , O‐1812 treated NMDA damage was limited to 20 ± 0.1 % compared to a 40 ± 0.1 % loss in retinal function with NMDA alone ( p<0.05 ). Topical O‐1812 effectively diffused into the AC and PC with concomitant decreases in IOP and retinal damage. With this integrated approach it is possible to model in vivo topical ocular PK and PD. Supp. in part by the Richmond Eye & Ear Fdn and NIH # DA009789 .