METABOLISM OF BW-1370U87 IN RAT, DOG, AND MAN

BW 1370U87 is a potent, selective inhibitor of rat and human brain MAO -A. The plasma concentrations of BW 1370U87 and its metabolites were d etermined in rat, dog, and man. After an oral dose, BW 1370U87 undergo es extensive first-pass metabolism in all species studied. The 1-(1,2, dihydroxyethyl) metabolite, BW 1003U88, was a major metabolite in rat, dog, and human plasma. The 1-(1-hydroxyethyl) metabolite, BW 183U88, was a major metabolite in dog plasma, whereas it was present in much l ower concentrations in the rat and man. Both BW 1003U88 and BW 183U88 are active MAO-A inhibitors although not as active as the parent compo und. The inactive 1-(2-acetic acid) metabolite, BW 1552U88, was a majo r metabolite in rat plasma but a minor metabolite in the dog. Plasma c oncentration versus time profiles in both rat and man suggest that the metabolites undergo enterohepatic recycling. Although plasma concentr ations of BW 1370U87 were relatively low compared to the metabolites, the concentrations detected in rat and man after a 50 mg/kg or 400 mg oral dose, respectively, exceeded the IC50 value measured in rat and h uman brain. Furthermore, the time course of MAO-A inhibition appears t o follow the plasma concentration versus time profile of BW 1370U87 in the rat. Preliminary experiments in rats indicate that BW 1370U87 and its metabolites distribute into brain and inhibit MAO-A.