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H Atluri, AK Mitra; Effect of Lipophilicity on Vitreous Disposition of Short-Chain Aliphatic Alcohols in Rabbits Using Ocular Microdialysis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2298.
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Purpose: The physiological barriers of the eye limit drug delivery to the posterior segment of the eye via topical or systemic administration. Intravitreal administration has proven to be safe and effective in the treatment of various vitreoretinal diseases. Elimination of drugs from the vitreous body can be via aqueous drainage or through the retina. Drugs eliminating predominantly through the aqueous pathway have higher half-lives and results in prolonged therapeutic action in the posterior segment of the eye. Therefore it is important to study the effect of physicochemical properties of the drugs on their elimination characteristics from the vitreous. The purpose of this study is to determine the effect of lipophilicity on vitreous disposition of short-chain aliphatic alcohols. Methods: Radiolabeled (C14) methanol, 1-propanol, 1-pentanol, 1-hexanol and 1-heptanol with log Pc values ranging from -0.77 to 2.7 were studied. New Zealand albino rabbits weighing 2-2.5 kg were used. Microdialysis probes were implanted in both anterior and posterior chamber to sample aqueous and vitreous humor simultaneously. Concentric probe was implanted in vitreous chamber about 3 mm below the cornealscleral limbus. Linear probe was implanted in the anterior chamber using a 25G needle. Isotonic phosphate buffer saline (pH 7.4) was perfused through the probe with a flow rate of 2µl/ml using a CMA/100 microinjection pump. Alcohols (2.030 mcg to 130.72 mcg) were injected into the vitreous body. In vitro recovery for the probes was calculated using respective alcohols in isotonic phosphate buffer saline. Pharmacokinetic parameters were determined by non-linear regression analysis (Win-Nonlin). Results: Vitreal elimination half-lives of methanol, 1-propanol, 1-pentanol, 1-hexanol and 1-heptanol are 51.99±5.7, 58.53±5.8, 72.92±5.8, 119.70±12.82, and 153.71±21.6 min, respectively. AUC(0-inf)/Dose values for methanol, 1-propanol, and 1- pentanol in aqueous humor are 0.3379±0.134, 0.283±0.119, and 0.292±0.048 mcg.min/ml/mcg, respectively. Aqueous levels for methanol, 1-propanol, and 1-pentanol were observed to be similar in anterior chamber. Alcohol levels for 1-heptanol were not detectable in the anterior chamber with the dose administered in the vitreous.Conclusion: The shorter vitreal elimination half-lives of these alcohols suggest retinal route of elimination. The elimination rate of alcohols studied from the vitreous has observed to be decreasing with increase in lipophilicity.
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