Metabolic Fate of Dorzolamide, a New Carbonic Anhydrase Inhibitor. (I): Absorption, Distribution, Metabolism and Excretion of (14C)Dorzolamide after Single Administration to Rats.

Abstract

The absorption, distribution, metabolism and excretion of [14C]dorzolamide hydrochloride (MK-507) were studied in rats after single administration. In vitro plasma protein binding was also investigated.1. Following intravenous administration of [14C]dorzolamide hydrochloride to male rats at doses ranging from 0.1 to 5 mg/kg, blood AUC values increased proportionally with doses up to 0.5 mg/kg, but no increase in the values was observed for the dose range of 1 to 5 mg/kg. Most of the radioactivity in blood was present in erythrocytes. The elimination of radioactivity from the blood was very slow and the estimated t1/2 was 10.5-11.3 days.2. No sex differences were observed in blood concentration profiles regardless route of administration, oral or intravenous. After oral administration, almost all [14C]dorzolamide was absorbed.3. After intravenous administration at the dose of 0.5 mg/kg, most of the radioactivity was distributed in blood. At 30 min after dosing, the highest radioactivity was found in the kidney, followed by lung, spleen, bone marrow, stomach, liver, caecum and large intestine. The concentration-time profiles of most tissues were similar to that of blood.4. Within 31 days after intravenous administration at the dose of 0.5 mg/kg, the excretion of radioactivity accounted for 74.7% in urine and 11.8% in feces. Within 24 hr after oral administration at the dose of 0.5 and 5 mg/kg, 24.7 and 73.8% of administered radioactivity were excreted in urine, respectively.5. N-deethylated dorzolamide was found in the blood, urine and tissues. The ratio of the radioactive N-deethylated metabolite to the total radioactivity in blood or in tissues after administration at the dose of 5 mg/kg was larger than those after dosing at the dose of 0.5 mg/kg.6. The in vitro binding of dorzolamide and N-deethylated dorzolamide to plasma proteins accounted for less than 30% in all species studied, and these compounds were mainly bound to albumin.