Disposition of short-chain aliphatic alcohols in rabbit vitreous by ocular microdialysis

Abstract

Anatomic and physiological barriers limit drug delivery to the posterior segment of the eye via topical or systemic administration. Intravitreal administration has proven to be a safe and effective means of treating various posterior segment diseases. Elimination of a compound from the vitreous chamber may depend on lipophilicity, diffusivity, and aqueous solubility. This information is critical for optimizing intravitreal dosing which in turn can aid in the design of drug delivery systems. The purpose of this study is to determine the vitreous disposition of an ascending homologous series of short chain aliphatic alcohols ranging from hydrophilic methanol to lipophilic 1-heptanol by microdialysis. Radiolabelled 14C-methanol, 14C-1-propanol, 14C-1-pentanol, and 14C-1-heptanol with log partition coefficient values ranging from −0·77 to 2·7 were studied. Microdialysis probes were implanted in both anterior and vitreous chamber of the rabbit eye to sample aqueous and vitreous humors 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 25-guage needle. Isotonic phosphate buffer saline (IPBS) (pH 7·4) was perfused through the probe with a flow rate of 2 μl ml −1. Alcohols (2·0 μg–130·72 μg) were injected into the vitreous body. In vitro recovery for the probes was calculated using respective alcohols in IPBS. Pharmacokinetic parameters were determined by non-compartmental analysis. Vitreal elimination half-lives of methanol, 1-propanol, 1-pentanol and 1-heptanol are 52·0±5·7, 58·5±5·8, 72·9±5·8 and 153·7±21·6 min, respectively. Dose normalized area under the aqueous concentration time curve values of methanol, 1-propanol and 1-pentanol are 33·8±13·4, 28·3±11·9 and 29·2±4·9 μg min ml −1 μg −1 10 −2, respectively. Time taken to reach maximum concentration in the anterior chamber for methanol, 1-propanol and 1-pentanol is 120±42, 160±26, and 260±26 min, respectively. The maximum concentration of methanol, 1-propanol and 1-pentanol achieved in the anterior chamber is 18·6±10·3, 9·4±3·2, and 5·9±1·3 μg ml −1 10 −4 respectively. Detectable 1-heptanol levels were not observed in the anterior chamber with the intravitreal dose administered. The shorter vitreal elimination half-lives of the alcohols studied suggest retina as major route of elimination from the vitreous body. The elimination rate constants of alcohols from the vitreous appear to be progressively decreasing with ascending chain length and lipophilicity (methanol to 1-heptanol). Among the alcohols studied, methanol produced the highest concentration in the anterior chamber following vitreal administration.