Conroy C W, Maren T H
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville 32610, USA.
Exp Eye Res. 1995 Aug;61(2):213-22. doi: 10.1016/s0014-4835(05)80041-7.
Ampholyte carbonic anhydrase inhibitors (including MK-927) have previously been shown to elicit greater intraocular pressure reduction when applied in ionized form at moderately acidic or alkaline pH compared to application of un-ionized drug at neutral pH. Since ionized solutions should be far more membrane-impermeant than un-ionized solutions, we attempted to solve this apparent paradox. We studied the distribution at 0.5-18 hr of MK-927 in eye tissues and fluid after topical instillation of one drop of a 0.5% solution at pH 4.9, 7.0 and 9.1. Measured drug concentrations at 30 min in corneal epithelium and stroma are approximately 4.5-fold greater after acidic or alkaline application than after neutral application, with the highest levels being found in corneal epithelium. The same pattern is seen in ciliary process, the site of aqueous humor production. Here drug concentration is approximately 60% of that in cornea at 30 min. Free drug concentrations in ciliary process were used to compute the time course of maximal carbonic anhydrase inhibition for the three modes of application. Drug concentration in sclera, uvea and aqueous humor at all times are all low by comparison, suggesting drug movement is from cornea to ciliary process via the corneo-scleral junction. The k(in) for proton movement across the corneal epithelium was measured (k(in) = 12.4 hr-1) from which a permeability coefficient (P = 2.7 x 10(-2) cm sec-1) was computed. Separate analysis was made of the pH status of the cornea 30 min and 1 hr following instillation of 1 drop 2% acidic (pH 4.9) and alkaline (pH 9.1) MK-927, with sodium sulfadiazine and pilocarpine.HCl as pH controls. Stromal bicarbonate at 30 min was approximately halved after acidic drops and doubled after alkaline drops consistent with pH decrease or increase of nearly 0.3 U. The results are in accord with classical schemes for amine permeation of the cornea at acidic pH when consideration is given to movement of acid equivalents and corneal pH. Thus drug inside the eye is in relatively (> 95%) lipophilic form except that trapped in the cornea shortly after acidic or alkaline applications.
两性电解质碳酸酐酶抑制剂（包括MK - 927）先前已表明，与在中性pH下应用非离子化药物相比，在适度酸性或碱性pH下以离子化形式应用时能引起更大程度的眼压降低。由于离子化溶液的膜通透性应远低于非离子化溶液，我们试图解决这一明显的矛盾。我们研究了在pH值为4.9、7.0和9.1时局部滴注一滴0.5%溶液后，MK - 927在眼组织和房水中0.5 - 18小时的分布情况。在酸性或碱性应用后30分钟，角膜上皮和基质中的测量药物浓度比中性应用后大约高4.5倍，最高水平出现在角膜上皮中。在房水产生部位睫状体中也观察到相同的模式。在这里，30分钟时药物浓度约为角膜中的60%。利用睫状体中的游离药物浓度来计算三种应用模式下最大碳酸酐酶抑制的时间进程。相比之下，巩膜、葡萄膜和房水中的药物浓度在所有时间都很低，这表明药物是通过角膜 - 巩膜交界处从角膜向睫状体移动。测量了质子跨角膜上皮的k(in)（k(in) = 12.4 hr-1），并据此计算出渗透系数（P = 2.7 x 10(-2) cm sec-1）。分别分析了滴注1滴2%酸性（pH 4.9）和碱性（pH 9.1）MK - 927以及作为pH对照的磺胺嘧啶钠和毛果芸香碱盐酸盐后30分钟和1小时角膜的pH状态。酸性滴眼后30分钟基质中的碳酸氢盐大约减半，碱性滴眼后加倍，这与pH值降低或升高近0.3 U一致。当考虑酸当量的移动和角膜pH值时，结果与酸性pH下胺类渗透角膜的经典模式相符。因此，除了在酸性或碱性应用后不久被困在角膜中的药物外，眼内的药物相对（＞95%）呈亲脂性形式。
