Entero-hepatic Circulation of SM-10888 in the Rat: Elucidation of the Participating Major Metabolites

The entero-hepatic circulation of 9-amino-8-fluoro-1, 2, 3, 4-tetrahydro-2, 4-methanoacridine citrate (SM-10888) in rats was investigated after oral administration and/or duodenal infusion of a pooled bile sample. 1. Pooled bile obtained from a rat receiving an oral dose of 14C-SM-10888 (5 mg/kg) was infused into the duodenum of bile-duct cannulated rats. At 72 hr after starting infusion, percentage values for infused radioactivity excreted into the urine (23%) and bile (41%) indicated that at least 64% of the radioactivity in the bile was reabsorbed. 2. Infused bile contained the N-glucuronide of SM-10888 (SMG, 15%) and the O-glucuronide of the hydroxylated metabolite M3 (M3G, 42%). In the urine and bile from rats receiving infusion of the pooled bile sample, the M3G was the major component. 3. After oral administration of 14C-SM-10888, M3G level in the urine from non-operated rats (24% of dose) was greater than from bile-duct cannulated rats (10% of dose), reflecting reabsorption of metabolites in the bile and excretion as M3G. 4. SMG and M3G, present in the infused bile sample, liberated unconjugated SM-10888 and M3 after incubation with intestinal contents. Therefore it was assumed that the enterohepatic circulation included hydrolysis of SMG and M3G in the bile to SM-10888 and M3 by intestinal flora, reabsorption from gastrointestinal tract and subsequent further metabolism to M3G.