Pharmacokinetics, Acid-Base Balance and Intraocular Pressure Effects of Ethyloxaloylazolamide—A Novel Topically Active Carbonic Anhydrase Inhibitor

Abstract

Studies evaluated a novel series of biscarbonylamides of 2-amino-1,3,4-thiadiazole-5-sulfonamide (2-ATS) for topical use as ocular hypotensive carbonic anhydrase inhibitors (CAI). Transcorneal accession rate constants (kin) for ethyloxaloylazolamide (EtOxAz), ethylsuccinylazolamide (EtSuxAz) and ethyladipoylazolamide (EtAdipAz), and activity against carbonic anhydrase (CA) were determined in vitro by an enzymatic assay and High Performance Liquid Chromatography (HPLC). The ocular hypotensive effect was measured by pneumatonometry on conscious normotensive New Zealand White (NZW) rabbits, using masked, randomly assigned paired-eye design for treatment vs. control. At various time points following treatment, aqueous humor, ciliary processes and corneal buttons were collected and assayed for drug concentrations using enzymatic assay and HPLC.Transcorneal accession rates for the novel compounds were 1·5 to 18 times that of the parent compound, acetazolamide (Actz). The activity factor for EtOxAz was 72·8 × 103 hr-1 of 23 times that of Actz. The activity factors for EtSuxAz and EtAdipAz were 6·8 and 1·1 × 103 hr-1, respectively. Subcutaneous administration of EtOxAz, EtSuxAz, and EtAdipAz, in 225 μmol kg-1 concentrations, induced a significant decrease in the intraocular pressure (IOP) at 1 hr post injection of 4, 5·8 and 6 mmHg for EtOxAz, EtSuxAz and EtAdipAz, respectively (P < 0·05 for each). Topical application of 75 mM EtOxAz lowered the IOP by 3·0 mmHg (P < 0·05). This effect was maximal after 60 min and persisted for at least 5 hr. EtSuxAz and EtAdipAz did not alter the IOP significantly when given topically.Subcutaneous administration of the three compounds was associated with acidosis (pH as low as 7·21). Topical application did not cause any changes in the acid-base balance. There was a direct correlation between the amount of drug delivered to the ciliary process and the magnitude of ocular hypotensive effect. Following topical application EtOxAz reached the ciliary epithelium in concentrations sufficient to inhibit more than 99·95% of the ciliary carbonic anhydrase (> 8 μM), while plasma drug concentrations were below the limit of detection by the assay (< 0·2 μM). Within the first hour after topical application, half of the EtOxAz was eliminated from the anterior uvea.In summary, EtOxAz is a topically effective CAI. Structural modifications of thiadiazole sulfonamides, with the increase of both water and lipid solubilities, improved the transcorneal accession while preserving sufficient CA inhibitory activity, resulting in a significant IOP decrease following topical application of EtOxAz. EtOxAz reaches the ciliary body in concentrations sufficient to induce its ocular hypotensive effect, without significant systemic absorption or alteration of the acid-base balance.