WHOLE-BLOOD PHARMACOKINETICS AND METABOLIC EFFECTS OF THE TOPICAL CARBONIC-ANHYDRASE INHIBITOR DORZOLAMIDE

Following a single-dose, open-label, pilot pharmacokinetic study in si x subjects, the systemic pharmacokinetics and metabolic effects of dor zolamide after topical ocular administration were investigated in a do uble-blind, randomised, placebo-controlled study in 12 healthy volunte ers. The subjects received a controlled diet on the 5 days before trea tment initiation and throughout the study. For 14 days, a bilateral q. i.d. regimen of 3% dorzolamide, consisting of approximately 7.7 mu g p er day (21.3 mu mol) dorzolamide hydrochloride, or placebo was given. Blood and urine electrolytes and acid-base profiles were measured 1 da y prior to treatment and on days 1, 7 and 14 of treatment, and 24-h ur ine samples were collected daily. Topically applied dorzolamide was sl owly taken up in erythrocytes and eliminated with a half life of appro ximately 120 days. Compared to the pre-study values, no significant tr eatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium and citrate excretions. Two other volunt eers given acetazolamide (125 mg q.i.d.) and assessed with the identic al set of observations demonstrated marked metabolic changes. In spite of the prolonged and marked inhibition of carbonic anhydrase in red b lood cells by dorzolamide, clinically significant metabolic and renal effects were not observed. The ocular tolerability profile was accepta ble to all subjects.