Ocular Absorption, Blood Levels, and Excretion of Dorzolamide, a Topically Active Carbonic Anhydrase Inhibitor

Abstract

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.

The effects of dorzolamide 2% and dorzolamide/timolol fixed combination on retinal and optic nerve head blood flow in primary open-angle glaucoma patients

“…23 Dorzolamide is one of the most commonly used molecules in combination therapy (D/T) with timolol. This drug lowers IOP by inhibiting carbonic anhydrase isoenzymes II and IV in the ciliary processes 24,25 with minimal systemic and ocular side effects. 23 Dorzolamide could have a positive effect on retinal and peripapillary haemodynamics owing to its ability to induce local metabolic acidosis and consequently relax arteriolar pericytes.…”

Carbonic Anhydrase Inhibitors: Synthesis of Sulfonamides Incorporating 2, 4, 6–Trisubstituted-Pyridinium-Ethylcarboxamido Moieties Possessing Membrane-Impermeability and in Vivo Selectivity for the Membrane-Bound (CA IV) Versus the Cytosolic (CA I and CA II) Isozymes

“…Sulfonamides 1-26 used in synthesis were either commercially available compounds (from Sigma, Acros or Aldrich) or were prepared as described previously: 4-hydrazino-benzenesulfonamide 4 by diazotization of sulfanilamide followed by reduction of the diazonium salt with tin(I1) chloride;26 halogenosulfanilamides 7-10 by halogenation of sulfanilamide as reported in the 1iteratu1-e;~' compound 16 from 5-amino-1,3,4-thiadiazole-2-sulfonamide (obtained from acetazolamide)28 by acylation with the phthalimido-derivative of P-alanine, followed by hydrazin~lysis,~~ and the imine 15 by deprotection of methazolamide with concentrated hydrochloric acid.30 Aminobenzolamide 17 and the corresponding thiadiazoline 18 were obtained as reported in Ref. [31], the sulfanilyl-sulfanilamide 19 and its rneta-derivative 20 as reported in Ref.…”

Pharmacotherapy and Adherence Issues in Treating Elderly Patients with Glaucoma

“…3.3 study, the plasma concentration of dorzolamide, after topical administration, was only 0.034 lM, 1/700 that of the red cell concentration and 1/200 of that needed for the systemic side effects, which can develop following systemically administered acetazolamide[61].…”