IRREVERSIBLE BINDING TO PROTEINS AFTER SINGLE AND REPEATED DAILY ORAL-ADMINISTRATION OF 4-(2,2-DIPHENYLETHYL) IMIDAZOLE (SC-46264) TO THE CYNOMOLGUS MONKEY

SC-46264 is an antagonist of the alpha(2)-adrenergic receptor. Distrib ution and excretion of [C-14]-SC-46264 were studied after single and r epeated daily oral administrations to the Cynomolgus monkey at a 1.5 m g/kg dose. After a single oral administration, more than 95% of the ad ministered dose was recovered within 48 h in the urine (+/- 60%) and f aeces (+/- 40%). Approximately 1.7% remained in the gastro-intestinal (GI) tract and 2% in the animal body. However,the radioactivity remain ing in the animal body decreased very slowly from 2 to 1% between 48 a nd 144 h. An accumulation of very small amounts of radioactivity could be suspected in the plasma, the liver, the thyroid, the adrenals and the kidneys. In a 2 week daily oral administration of [C-14]-SC-46264, the amount of total radioactivity remaining in the animal body 24, 48 and 216 h after the last administration was approximately 21, 11 and 5% of the daily administered dose, respectively. It confirmed the accu mulation of [C-14]-SC-46264 related compound in the plasma, the liver, the thyroid, the adrenals and the kidneys. The minimum plasma concent rations of total radioactivity observed before each administration inc reased during the treatment and apparently did not yet reach an equili brium after 14 days. In these plasma samples obtained throughout the s tudy, an increasing fraction of the total radioactivity could not be e xtracted and was recovered with precipitable material. These observati ons lead to the hypothesis of an irreversible binding of some material to the proteins. To confirm that hypothesis based on the in vivo data , a 1 h in vitro bioactivation of [C-14]-SC-46264 with rat liver micro somes was conducted. It showed that 4.6% of the [C-14]-SC-46264 total radioactivity used in the experiment could bind irreversibly to the pr oteins. This binding was highly reduced by an inhibitor of the cytochr ome mixed function oxidase or a free radical scavenger. This observati on is consistent with a cytochrome P-450 dependent production of a [C- 14]-SC-46264 reactive intermediate that can covalently bind to protein s during the phenyl hydroxylation observed with that compound.