Brechue W F, Maren T H
University of Florida Health Science Center, College of Medicine, Department of Pharmacology and Therapeutics, Gainesville 32610-0267.
Exp Eye Res. 1993 Jul;57(1):67-78. doi: 10.1006/exer.1993.1100.
We have assessed the onset and duration of decreased intraocular pressure and aqueous humor flow contrasting systemic and topical administration of carbonic anhydrase inhibitors. The relationship between physiological effects and fractional activity of carbonic anhydrase isoenzymes in the eye was also investigated. Experiments were performed in normotensive New Zealand white rabbits. Intraocular pressure was determined manometrically or tonometrically and aqueous humor flow by sulfacetamide clearance. We studied methazolamide (25 mg kg-1), ethoxzolamide (4 mg kg-1), and MK-927 (2% in 0.5% hydroxyethylcellulose, topical, pH 4.8). There is an immediate reduction in intraocular pressure (1.2 and 1.8 mmHg by 2 min) and aqueous flow (33% and 40% by 5 min) following intravenous dosing with either methazolamide or ethoxzolamide. This correlates with rapid appearance of drug in the anterior uvea and very low fractional activity of ocular carbonic anhydrase isoenzymes II (cytosolic) and IV (membrane bound). Peak intraocular pressure reduction averaged 4.2 +/- 0.68 mmHg and 4.5 +/- 0.8 mmHg for methazolamide and ethoxzolamide at 60 and 45 min, respectively. Peak flow reduction was 38% for methazolamide and 40% for ethoxzolamide, at 5 min. Aqueous flow and intraocular pressure returned to baseline at 7 and 4 hr following methazolamide and ethoxzolamide, respectively. This corresponds to decay of drug from ocular tissues and significant increases in fractional activity of carbonic anhydrase isoenzymes. Topical MK-927 resulted in a 1.2 mmHg decrease in pressure by 5 min. This correlated with the early appearance of drug in the anterior uvea prior to its appearance in aqueous humor and very low fractional activity of carbonic anhydrase isoenzymes. Intraocular pressure decreased 3.6 +/- 0.35 mmHg at 1 hr and returned to baseline by 6 hr. Aqueous flow was reduced 12% by 5 min and 35% at 1 hr. The appearance of MK-927 in the anterior uvea prior to detection in aqueous suggests a significant non-corneal route of absorption following topical administration. Topical MK-927 results in a more gradual reduction in intraocular pressure and flow, although peak effects are not statistically different from systemic carbonic anhydrase inhibitors. The time of pressure return to baseline is also comparable to systemic carbonic anhydrase inhibitors. Because the relations between carbonic anhydrase II and carbonic anhydrase IV in the ciliary process are not yet clear and since the drugs have different affinities for the isozymes, the precise degree of fractional inhibition necessary for pharmacological effect is not certain, but based on drug concentration in the anterior uvea, may take 98% inhibition for full intraocular pressure reduction.
我们对比了碳酸酐酶抑制剂全身给药和局部给药时眼内压降低及房水生成减少的起始时间和持续时间。同时还研究了眼内碳酸酐酶同工酶的生理效应与活性分数之间的关系。实验在血压正常的新西兰白兔身上进行。通过测压法或眼压测量法测定眼内压，通过磺胺醋酰清除率测定房水生成。我们研究了甲醋唑胺（25毫克/千克）、乙氧唑胺（4毫克/千克）和MK-927（0.5%羟乙基纤维素中2%，局部用药，pH值4.8）。静脉注射甲醋唑胺或乙氧唑胺后，眼内压立即降低（2分钟时分别降低1.2和1.8毫米汞柱），房水生成减少（5分钟时分别减少33%和40%）。这与药物在前葡萄膜中迅速出现以及眼内碳酸酐酶同工酶II（胞质）和IV（膜结合）的极低活性分数相关。甲醋唑胺和乙氧唑胺在60分钟和45分钟时，眼内压降低峰值平均分别为4.2±0.68毫米汞柱和4.5±0.8毫米汞柱。5分钟时，甲醋唑胺和乙氧唑胺的房水生成减少峰值分别为38%和40%。甲醋唑胺和乙氧唑胺给药后，房水生成和眼内压分别在7小时和4小时恢复到基线水平。这与药物从眼组织中消退以及碳酸酐酶同工酶活性分数显著增加相对应。局部应用MK-927在5分钟时使眼压降低1.2毫米汞柱。这与药物在前葡萄膜中比在房水中更早出现以及碳酸酐酶同工酶的极低活性分数相关。1小时时眼内压降低3.6±0.35毫米汞柱，6小时时恢复到基线水平。5分钟时房水生成减少12%，1小时时减少35%。局部给药后，MK-927在前葡萄膜中先于在房水中被检测到，这表明存在一条重要的非角膜吸收途径。局部应用MK-927导致眼内压和房水生成的降低更为缓慢，尽管峰值效应与全身碳酸酐酶抑制剂在统计学上无差异。眼压恢复到基线水平的时间也与全身碳酸酐酶抑制剂相当。由于睫状体中碳酸酐酶II和碳酸酐酶IV之间的关系尚不清楚，且这些药物对同工酶的亲和力不同，因此产生药理效应所需的精确抑制分数程度尚不确定，但根据前葡萄膜中的药物浓度，可能需要98%的抑制才能使眼内压完全降低。
