Pharmacokinetics and disposition of memantine in the arterially perfused bovine eye.
OBJECTIVE
To develop an improved ((1)This is to clearly acknowledge that we have tried to improve an existing model.) arterially perfused bovine eye model and investigate the general ocular disposition of memantine.


METHODS
Fresh bovine eyes were prepared by exposing and cannulating one ciliary artery, placing the eye into a perfusion chamber and slowly increasing the rate of perfusion to 1.0 ml/min. Analysis of the arterial perfusion pressure (APP), intraocular pressure (IOP), venous perfusate for glucose consumption and lactate dehydrogenase (LDH) activity, and histopathology ensured viability. Memantine was administered with the perfusate (simulated systemic access), by an intravitreal injection and by topical infusion. At the appropriate time points, the cornea, aqueous humour, sclera, iris-ciliary body, choroid/RPE, retina and vitreous humour were harvested and analysed for memantine.


RESULTS
The preparation remained viable for at least 9 h. At this time, histopathological examination showed mild to moderate deterioration of retinal layers. However, all retinal layers remained well defined and the integrity of the inner limiting membrane and Bruch's membrane were preserved. Glucose consumption, LDH levels and constant APP and IOP showed that correct cannulation and viability was maintained. After administration, memantine accumulated in the melanin rich iris-ciliary body and choroid/RPE. Results following topical administration indicate that substantial concentrations of memantine are present in the retina and choroid/RPE.


CONCLUSIONS
The arterial perfused bovine eye system proved to be a useful system for ocular drug delivery studies. The experimental results indicate that memantine will accumulate in the posterior segment when delivered by the topical route and that melanin-binding may support sustaining significant concentrations in the retina.
Koeberle
Martin J
MJ
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, UK.
Hughes
Patrick M
PM
Skellern
Graham G
GG
Wilson
Clive G
CG
D000818:Animals; D001158:Arteries / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005123:Eye / Q000098:blood supply* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007429:Intraocular Pressure / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D013058:Mass Spectrometry; D008559:Memantine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010477:Perfusion; D012039:Regional Blood Flow / Q000502:physiology; D013056:Spectrophotometry, Ultraviolet
D018691:Excitatory Amino Acid Antagonists; D007202:Indicators and Reagents; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D008559:Memantine