ALPRAZOLAM METABOLISM IN-VITRO - STUDIES OF HUMAN, MONKEY, MOUSE, ANDRAT-LIVER MICROSOMES

Biotransformation of the triazolobenzodiazepine alprazolam (ALP) was s tudied in vitro using hepatic microsomal preparations from human, monk ey, mouse, and rat liver tissue. Two principal hydroxylated metabolite s were identified: 4-hydroxy- and alpha-hydroxy-alprazolam (4-OH-ALP a nd alpha-OH-ALP). In all species, rates of 4-OH-ALP formation exceeded those of alpha-OH-ALP. In human liver microsomes, ratios of 4-OH-ALP/ alpha-OH-ALP reaction velocities calculated at clinically relevant pla sma concentrations of ALP ranged from 7 to 17, qualitatively consisten t with, but numerically larger than, the ratio of the plasma levels of the two metabolites during clinical use of ALP in humans. K(m) values for both 4-OH-ALP (170-305 muM) and alpha-OH-ALP (63-441 muM) conside rably exceeded' the usual maximum plasma concentration observed in hum ans (200 ng/ml, 0.65 muM), consistent with the linear (dose-independen t) pharmacokinetic characteristics of ALP observed in humans. Thus for mation of 4-OH-ALP via hydroxylation is the major route of ALP metabol ism. This pathway is probably mediated by the cytochrome P-450-3A subf amily. Factors that impair the activity of this cytochrome subtype are likely to impair clearance of ALP in vivo.