Studies on the Metabolic Fate of Neticonazole. (I): Absorption, Distribution, Metabolism and Excretion in Rats after a Single Subcutaneous Administration.

Abstract

The absorption, distribution, metabolism and excretion of 14C-neticonazole (14C-SS717) were studied in rats after a single subcutaneous administration of 25mg/kg.1. Blood levels of the radioactivity reached the maximum of 2.Olμg equiv. of SS717/ml (male) or 1.59μg equiv. of SS717/ml (female) at 4hr after dosing, and then declined slowly during 4 ?? 24hr with half-lives of 21 and 15hr in male and female rats, respectively. The elimination half-lives at the terminal phase (48 ?? 168hr) were 64hr (male) and 58hr (female).2. Within 120hr after dosing in male rats, 65.4 and 29.5% of the dose were excreted in the urine and feces, respectively. No sex difference was observed in the excretion of radioactivity.3. Biliary excretion of the radioactivity within 48hr after dosing was 51.9 and 46.7% in male and female rats. respectively. In male rats, 46. 7 and 2.0% of the dose were excreted in the urine and feces, respectively, while the excretion of radioactivity in female rats was 49. 6% of the dose in the urine and 2.7% of the dose in the feces. Also, the partial reabsorption of biliary excreta occurred from the intestinal tract.4. Maximum levels of the radioactivity in most of tissues were reached at 4hr after dosing in male rats, and a high level of the radioactivity was observed in the adrenal gland, liver, kidney, aorta, fat and harderian gland. The distribution of radioactivity in the stomach was also visualized by the whole body autoradiography.5. The extent of in vitro binding of 14C-SS717 to plasma proteins was 98.7 ?? 99.0% in rats, and 99.2-99.7% in human. The percent of in vivo binding of 14C-SS717 and/or its radioactive metabolites to the rat plasma proteins were 62.0-79.3% within 24hr after dosing.6. In the plasma samples drawn from male rats at lhr after dosing, the percent of radioactivity of the unchanged drug was 20.5% and that of U-1 ?? U-3, U-5, U-6 and M3 metabolites were 1.9 ?? 7.8%. Subsequently, the unchanged drug declined gradually, but the most of metabolites increased until 4hr after dosing and thereafter declined.In the urine excreted within 24hr after dosing, the percent of radioactivity of U-2 and U-6 metabolites were 17.1 and 14.1%, respectively, and that of U-1, U-3 ?? U-5 and five unknown metabolites were 0.5 ?? 9.7%. In the bile sample excreted within 24hr after dosing, the percent of radioactivity in U-2, U-5, U-6 and six unknown metabolites were 0. 2-2.2%. Meanwhile, in the enzymatically hydrolyzed samples, that of U-5, U-3, U-2, U-6 and 12 unknown metabolites were 0.59.5%, however, the most of those were observed for the first time.