In vitro metabolism of azasqualene derivatives and their effects on aminopyrine N-demethylase activity in rat liver microsomes

The metabolism of squalene dimethylamine (I), a potent inhibitor of 2,3-oxidosqualene (SO) cyclase, and of sixteen other squalene derivatives was investigated in rat liver microsomes. N-oxidation was the only metabolic pathway observed, squalene dimethylamine N-oxide being the only metabolite isolated from incubation of I. The azasqualane and quaternary ammonium derivatives did not form N-oxides during their metabolism. The inhibition of aminopyrine N-demethylase activity was also studied and the IC₅₀, for compound I, which shows weak competitive inhibition, was determined. At 1 mM concentration the other qualene derivatives showed a range of inhibition activity possibly due to their different lipophilicity.