Pharmacokinetics of indoramin and its 6-hydroxylated metabolite after repeated oral dosing

The pharmacokinetics of indoramin and its active 6-hydroxylated metabolite have been studied in healthy male volunteers after repeated oral dosing with 37.5 mg twice daily for 2 weeks. Plasma concentrations of indoramin accumulated, on average, three to four-fold above those anticipated on the basis of the kinetics after the first dose, though steady state was achieved by the end of the first week and no further increase was observed after 2 weeks. The degree of accumulation was consistent between subjects, with a highly significant (p < 0.001) correlation between the concentration 2 h after a single dose and the average steady-state concentration. Possible explanations for the accumulation of indoramin are discussed. Plasma concentrations of 6-hydroxyindoramin, in contrast, did not accumulate on multiple dosing. At steady state, concentrations of the metabolite, as represented by the AUC0–8h, were approximately 30–40 per cent of those of the unchanged drug. Since the two compounds are approximately equipotent the metabolite may accounts for 25 per cent of the hypotensive activity of indoramin during a typical clinical regime of 37.5 mg twice daily.