METABOLIC DISPOSITION OF C-14 VENLAFAXINE IN MOUSE, RAT, DOG, RHESUS-MONKEY AND MAN

1. The metabolic disposition of venlafaxine has been studied in mouse, rat, dog, rhesus monkey and man after oral doses (22, 22, 2, and 10 m g/kg, and 50 mg, respectively) of C-14-venlafaxine as the hydrochlorid e. 2. In all species, over 85% of the administered radioactivity was r ecovered in the urine within 72 h, indicating extensive absorption fro m the GI tract and renal excretion. 3. Venlafaxine was extensively met abolized, with only 13.0, 1-8, 7-9, 0.3 and 4.7% dose appearing as par ent compound in urine of mouse, rat, dog, monkey and man, respectively . The metabolite profile varied significantly among species, but prima ry metabolic reactions were demethylations and the conjugation of phas e I metabolites. Hydroxylation of the cyclohexyl ring also occurred in mouse, rat and monkey, and a cyclic product was formed in rat and mon key. Glucuronidation was the primary conjugation reaction, although su lphate conjugates were also detected in mouse urine. 4. While no metab olite constituted more than 20% dose in any species except man, the ma jor urinary metabolites were: mouse, N,O-didesmethyl-venlafaxine glucu ronide; rat, cis-1,4-dihydroxy-venlafaxine; dog, O-desmethyl-venlafaxi ne glucuronide; monkey, N,N,O-tridesmethyl-venlafaxine; and man, O-des methyl-venlafaxine.