2135 Systemic pharmacokinetics and carbonic anhydrase inhibition of dorzolamide

fir-pose: Dorzolamide @ORE) is a topical carbonic anhydrase (CA) inhibitor that is approved for treatment of open-angle glauccma and ocular hypertension. DORE exerts its effects directly in the eye at substantially lower doses and therefore with less systemic exposure than oral CA inhibitors To evaluate DORZ's potential for systemic CA inhibition, maximum systemic exposure was simulated through oral dosing in healthy subjects and rotally impaired patients. Methods: In one study, 8 healthy subjects received 2 mg DORZ pe, b.i.d. for 20 wks and in a separate study 9 subjects with mild to moderate renal impairment (creatininc clearance: 30-60 ml/min/1.73 m2) received the same dose for 24 wks. The oral route was chosen to reduce the dosing variability associated with topical ocular administration; the dose appmximstes the maxhnnm total systemic exposure possible from a daily dose of 2% DORZ, one drop OU t.i.d. Whole blood. plasma, and urine samples were collected weekly for the first I2 wks and biweekly thereafter in the healthy subject stndy and were collected biweekly after the first week in the renally impaired study. Both studies measured drug and Ndcscthyl metabolite ccnccntmtions in the RBCs, plasma, end urine; CA-iscenzyme II and total CA activity in RBCs; and clinical biochemical parameters in RBCs and urine. Results: DORZ and mctabclite accumulated in RBCs as a result of binding to intracellular CA. Steady-state levels of DOAZ were reached at 4 wks for drug and within 13-14 wks for metabolite in both studies. Plasma concentrations of DORZ and metabclite were generally below the level of dctcction (I5 nM) in healthy and 99% CA-II inhibition) or respiration (i.e. at least 96% total CA inhibition). Therefore, topical use of DORZ in healthy subjects and moderately renally impaired patients is not expected to canse the marked biochemical changes which can occur with oral CA inhibitors.