Chlorpromazine excretion in chronically dosed primates. I. Occurrence of a previously unreported class of chlorpromazine conjugates.

Abstract

The use of tritiated chlorpromazine to correlate total excretion of radioactivity with characterization of the radioactive metabolites had shown a substantial discrepancy. While radioactivity was totally excreted and accounted for within three weeks, recognizable chlorpromazine metabolites represented only about two thirds of the radioactivity in any given sample. To rule out tritium exchange, 14C-labeled chlorpromazine was administered to Rhesus monkeys. The same discrepancy was observed, primarily in the conjugated drug fraction. Therefore, all unconjugated chlorpromazine metabolites were exhaustively extracted, and an alkaline hydrolysis performed. The aglycones liberated thereby were again carefully removed, and the residual aqueous fraction was subjected to an acid hydrolysis. This procedure yielded an additional group of known and unknown phenolic chlorpromazine aglycones, representing approximately one third of the radioactivity in the whole urine. Preliminary trials on urine pools of patients chronically dosed with chlorpromazine yielded essentially the same results. The structure of this new class of chlorpromazine conjugates has not yet been elucidated, nor is the ligand known at this time. A glucoside-type bond may characterize this significant class of chlorpromazine.