Hepatic microsomal metabolism of the potential memory-enhancing agent, CL 275,838, to its desbenzyl derivative

1. The oxidation of the potential memory-enhancer and antidepressant agent CL 275,838 by rat liver microsomes was investigated. CL 275,838 was rapidly and extensively biotransformed in vitro to its desbenzyl derivative (II), the main metabolite observed in vivo No other known metabolites could be detected in the incubation mixture except for trace amounts of a hydrolysis product (IV).2. The formation of the desbenzylated derivative II required the presence of an NADPH-generating system and was significantly inhibited by carbon monoxide, SKF 525-A and cimetidine, indicating the participation of P450 in the oxidation of CL 275,838. The reaction was markedly enhanced by phenobarbital and by pregnenolone-16α-carbonitrile [particularly in the female]. β-Naphthoflavone did not significantly affect desbenzylation.3. Kinetic studies indicate that there are sex-dependent differences in CL 275,838 metabolism in vitro as observed in vivo in rat. Maximal velocity for the oxidation of CL 275,838 in microsomes isolated...