EFFECT OF ACYLATION ON THE OCULAR DISPOSITION OF ACYCLOVIR .2. CORNEAL PERMEABILITY AND ANTI-HSV-1 ACTIVITY OF 2'-ESTERS IN RABBIT EPITHELIAL KERATITIS

被引：30

作者：

HUGHES, PM ^{[1
]}

MITRA, AK ^{[1
]}

机构：

[1] PURDUE UNIV,SCH PHARM & PHARMACAL SCI,DEPT IND & PHYS PHARM,W LAFAYETTE,IN 47907

来源：

JOURNAL OF OCULAR PHARMACOLOGY | 1993年 / 9卷 / 04期

关键词：

D O I：

10.1089/jop.1993.9.299

中图分类号：

R77 [眼科学];

学科分类号：

100212 ;

摘要：

In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic acyl esters of acyclovir to determine the effect of lipophilicity on the transcorneal diffusion. Corneal membrane permeability coefficients increased with increasing lipophilicity of the straight chain aliphatic esters. The branch chain ester, acyclovir isobutyrate, displayed an anomalously low corneal permeability when compared to acyclovir esters having similar molecular size and 1-octanol/water partition coefficient. In vivo corneal penetration studies were conducted on unanesthetized rabbits. The aqueous humor concentrations of acyclovir and the ester prodrugs were measured at twenty five minutes after the topical instillation of an aqueous solution of the appropriate compound. The concentration of acyclovir in the aqueous humor increased with increasing 1-octanol/water partition coefficient. The lipophilic modification was shown to have a greater effect on increasing productive corneal absorption than the precorneal loss pathways. The effectiveness of acyclovir butyrate as a treatment for primary herpetic keratitis was evaluated in the McKrae strain infected rabbit model. The compound did not lose activity due to the esterification of the 2' hydroxyl group.

引用

页码：299 / 309

页数：11

共 21 条

[1]

Richard W., Darrell, (1985)

[2]

William H., Havener, (1983)

[3]

Williams H.P., Falcon M.G., Jones B.R., Corticosteroids in the management of herpetic eye disease, 97, pp. 341-349, (1977)

[4]

Shiota H., Inoue S., Yamane S., Efficacy of acycloguanosine against herpetic ulcers in rabbit comea, Br. J. Ophthalmol., 63, pp. 429-435, (1979)

[5]

Kaufman H.E., Vernell E.D., Centifanto Y.M., Effect of 9-(2-hydroxyethoxymethyl) guanine on herpesvirus induced keratitis and iritis, Antimicrob. Agents Chemother., 14, pp. 842-845, (1978)

[6]

Maudgal P.C., De Clercq K., Descamps J., Missotten L., Topical treatment of experimental keratouveitis with 2′-O-glycylacyclovir: A water soluable ester of Acyclovir, Arch Ophthalmol, 102, pp. 140-142, (1984)

[7]

Pavan-Langston D., Lass J., Hettinger M., Udell I., Acyclovir and vidarabine in the treatment of ulcerative herpes simplex keratitis, Am. J. Ophthalmol., 92, pp. 829-835, (1981)

[8]

Bungaard H., Falch E., Larsen C., Mosher G., Mikkelson T.J., Pilocarpine prodrugs I. Synthesis, physicochemical properties, and kinetics of lactonization of pilocarpic acid esters, J. Pharm. Sci., 75, pp. 36-43, (1986)

[9]

Bungaard H., Falch E., Larsen C., Mosher G., Mikkelson T.J., Pilocarpine prodrugs II, J. Pharm. Sci., 75, pp. 775-783, (1986)

[10]

Mosher G.L., Bungaard H., Falch E., Larsen C., Mikkelson T.J., Ocular bioavailability in pilocarpic acid mono- and diester prodrugs as assessed by miotic activity in the rabbit, Int. J. Pharm., 39, pp. 113-120, (1987)

← 1 2 3 →