Maren T H, Conroy C W, Wynns G C, Levy N S
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, USA.
J Ocul Pharmacol Ther. 1997 Feb;13(1):23-30. doi: 10.1089/jop.1997.13.23.
Dorzolamide is a powerful inhibitor of carbonic anhydrase (CA) II that penetrates the sclera and cornea to reach the ciliary process and lowers formation of HCO3 and aqueous humor. The usual dose applied to the eye in treatment of glaucoma is 1 drop (30 microL of 2% solution) every 8 hr to each eye, or a total daily dose of 4 mg. On this regime, the red cells accumulated drug over a period of 8 days, reaching a value of 20-25 microM, which corresponds to the concentration of CA II in human red cells. This drug concentration persisted throughout the 18 months of application. The plasma concentration was 0.034 microM, or 1/700 that of the red cells. This plasma concentration corresponds to that calculated from the dilution of administered drug into body water. The data are well fitted into the equilibrium expression for KI of dorzolamide against CA II at 37 degrees C, as 8 x 10(-9) M. The red cells also contain a small amount (5 microM) of the N-des-ethyl metabolite, probably reflecting its modest binding to CA I. In the initial 8-day drug period, virtually none appeared in the urine since CA II sites were being filled. At steady state, renal excretion was 1.3 mg/day and the renal clearance 90 ml/min. These excretion numbers include the small (20%) amount of the des-ethyl metabolite of dorzolamide. The relation of these data to lowering of intraocular pressure is clear. By the systemic route, an inhibitor such as acetazolamide is effective when free drug concentration in plasma is 2.5 microM. In the case of topical drugs, as shown here, the plasma concentration is some 100 x lower, but the concentration in ciliary process is 2-10 microM, comparable to that following systemic drugs (1). In conclusion, the concentration in plasma (reflecting free drug) of dorzolamide is about 1/200 of that needed for systemic effects as seen following acetazolamide or methazolamide. Thus, there is a clear pharmacological basis for the lack of any physiological effects of ocular dorzolamide, except on the eye itself.
多佐胺是一种强效碳酸酐酶（CA）II抑制剂，它可穿透巩膜和角膜到达睫状体，减少HCO3和房水的生成。治疗青光眼时，眼部常用剂量为每只眼每8小时滴1滴（30微升2%溶液），即每日总剂量为4毫克。在此用药方案下，红细胞在8天内积累药物，达到20 - 25微摩尔的浓度，这与人类红细胞中CA II的浓度相当。在整个18个月的用药期间，该药物浓度持续存在。血浆浓度为0.034微摩尔，是红细胞浓度的1/700。此血浆浓度与将给药药物稀释到体内水分中计算得出的浓度相符。这些数据很好地符合多佐胺在37℃时对CA II的KI平衡表达式，为8×10⁻⁹ M。红细胞中还含有少量（5微摩尔）的N - 去乙基代谢产物，这可能反映了它与CA I的适度结合。在最初的8天用药期内，由于CA II位点被填满，尿液中几乎没有药物出现。在稳态时，肾脏排泄量为1.3毫克/天，肾脏清除率为90毫升/分钟。这些排泄数据包括多佐胺去乙基代谢产物的少量（20%）。这些数据与眼压降低之间的关系很明显。通过全身途径，当血浆中游离药物浓度为2.5微摩尔时，像乙酰唑胺这样的抑制剂是有效的。在此处所示的局部用药情况下，血浆浓度约低100倍，但睫状体中的浓度为2 - 10微摩尔，与全身用药后的浓度相当（1）。总之，多佐胺的血浆浓度（反映游离药物）约为乙酰唑胺或甲醋唑胺全身作用所需浓度的1/200。因此，除了对眼睛本身外，眼部使用多佐胺缺乏任何生理效应有明确的药理学依据。
