Alprazolam metabolism in vitro: studies of human, monkey, mouse, and rat liver microsomes

Pharmacology. 1993 Oct;47(4):268-76. doi: 10.1159/000139107.


Biotransformation of the triazolobenzodiazepine alprazolam (ALP) was studied in vitro using hepatic microsomal preparations from human, monkey, mouse, and rat liver tissue. Two principal hydroxylated metabolites were identified: 4-hydroxy- and alpha-hydroxy-alprazolam (4-OH-ALP and 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 plasma concentrations of ALP ranged from 7 to 17, qualitatively consistent with, but numerically larger than, the ratio of the plasma levels of the two metabolites during clinical use of ALP in humans. Km values for both 4-OH-ALP (170-305 microM) and alpha-OH-ALP (63-441 microM) considerably exceeded the usual maximum plasma concentration observed in humans (200 ng/ml, 0.65 microM), consistent with the linear (dose-independent) pharmacokinetic characteristics of ALP observed in humans. Thus formation of 4-OH-ALP via hydroxylation is the major route of ALP metabolism. This pathway is probably mediated by the cytochrome P-450-3A subfamily. Factors that impair the activity of this cytochrome subtype are likely to impair clearance of ALP in vivo.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Alprazolam / metabolism*
  • Alprazolam / pharmacokinetics*
  • Animals
  • Biotransformation
  • Chromatography, High Pressure Liquid
  • Female
  • Humans
  • Macaca
  • Male
  • Mice
  • Microsomes, Liver / metabolism*
  • Middle Aged
  • Oxidation-Reduction
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity


  • Alprazolam