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首页> 外文期刊>Drug Metabolism and Disposition: The Biological Fate of Chemicals >Ocular pharmacokinetics of dorzolamide and brinzolamide after single and multiple topical dosing: implications for effects on ocular blood flow.
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Ocular pharmacokinetics of dorzolamide and brinzolamide after single and multiple topical dosing: implications for effects on ocular blood flow.

机译：单次和多次局部给药后多佐胺和布林酰胺的眼药代动力学：对眼血流量的影响。

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摘要

Ophthalmic carbonic anhydrase inhibitors have been shown to improve retinal and optic nerve blood flow. However, the relative tissue distributions of commercially available carbonic anhydrase inhibitors to the optic nerve are not known. The objective of this study was to compare the ocular pharmacokinetics and tissue distribution profiles of dorzolamide and brinzolamide after single and multiple topical applications. Pigmented rabbits were treated with single or multiple topical administrations of 30 mul of Trusopt (dorzolamide hydrochloride ophthalmic solution, 2%) to one eye and 30 mul of Azopt (brinzolamide ophthalmic suspension, 1%) to the other eye. Rabbits were euthanized at 10 predetermined time intervals over a period of 24 h, and ocular tissues and plasma samples were collected. For multiple dosing, rabbits were dosed twice per day with an 8-h interval between two doses, groups of rabbits were euthanized at 7, 14, and 21 days at 1 h after the last dose, and ocular tissues and plasma samples were collected. Drug levels in tissue samples were measured using liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters (C(max), T(max), and AUC(0-24)) were estimated by noncompartmental analysis. After a single dose, dorzolamide delivery (AUC(0-24)) to the aqueous humor, anterior sclera, posterior sclera, anterior retina, posterior retina, anterior vitreous, and optic nerve was 2-, 7-, 2.6-, 1.4-, 1.9-, 1.2-, and 9-fold higher than those of brinzolamide. C(max) was 2- to 5-fold higher for dorzolamide than that of brinzolamide in all of the ocular tissue. After multiple dosing, dorzolamide levels in the aqueous humor, sclera, retina, vitreous humor, and optic nerve were higher than those of brinzolamide, but statistical significance was achieved only with aqueous humor, vitreous humor, and optic nerve. Dorzolamide levels in the aqueous humor, anterior vitreous, posterior vitreous, and optic nerve were 1.4- to 3.2-, 2.4- to 2.7-, 2.2- to 4.5-, and 2.4- to 5.2-fold higher than those of brinzolamide. Upon multiple dosing, both drugs accumulated in all of the tissues except the conjunctiva, where the drug levels were lower than those observed with single dosing. No significant differences were found in the AUC values of these two drugs in the cornea and conjunctiva after single and multiple dosing. Drug levels were significantly higher in anterior regions than posterior regions in the sclera, retina, and vitreous for both drugs.
机译：眼科碳酸酐酶抑制剂已显示可改善视网膜和视神经的血流。但是，市售的碳酸酐酶抑制剂相对于视神经的相对组织分布是未知的。这项研究的目的是比较单次和多次局部应用后多佐胺和布林酰胺的眼药代动力学和组织分布特征。用一只或多只局部给药的色素兔子治疗30只眼的Trusopt（盐酸多佐酰胺眼用溶液，占2％）和另一只眼局部给药30 mul的Azopt（溴佐胺眼用混悬剂，占1％）。在24小时内以10个预定的时间间隔对兔子实施安乐死，并收集眼组织和血浆样品。对于多次给药，每天两次给兔子，两次剂量之间间隔8小时，最后一次给药后1小时的第7、14和21天对兔子组实施安乐死，并收集眼组织和血浆样品。使用液相色谱/串联质谱法测量组织样品中的药物水平。药代动力学参数（C（最大值），T（最大值）和AUC（0-24））通过非房室分析进行估算。单次给药后，将多佐胺（AUC（0-24））递送至房水，前巩膜，后巩膜，前视网膜，后视网膜，前玻璃体和视神经为2-，7-，2.6-，1.4-分别比苯佐酰胺高1.9倍，1.2倍和9倍。在所有的眼组织中，多佐胺的C（max）比苯佐酰胺的C（max）高2至5倍。多次给药后，房水，巩膜，视网膜，玻璃体液和视神经中的多佐胺水平高于布林酰胺，但只有房水，玻璃体液和视神经才具有统计学意义。房水，玻璃体前，玻璃体后和视神经中的多佐胺水平比青霉酰胺高1.4至3.2倍，2.4至2.7、2.2至4.5和2.4至5.2倍。多次给药后，除结膜外，所有药物均在所有组织中积聚，结膜的药物水平低于单次给药所观察到的水平。单次和多次给药后，这两种药物在角膜和结膜中的AUC值均无显着差异。两种药物的巩膜，视网膜和玻璃体前区药物水平均明显高于后区。

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