Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite

Pharmacogenomics J. 2002;2(4):243-58. doi: 10.1038/sj.tpj.6500115.


Cytochrome P450 (P450) is a superfamily of enzymes which mediates metabolism of xenobiotics including drugs. Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver by P4503A1 and P4503A4 respectively, to 4-hydroxy alprazolam (4-OHALP, pharmacologically less active) and alpha-hydroxy alprazolam (alpha-OHALP, pharmacologically more active). We examined P450 mediated metabolism of alprazolam by rat and human brain microsomes and observed that the relative amount of alpha-OHALP formed in brain was higher than liver. This biotransformation was mediated by a P450 isoform belonging to P4503A subfamily, which is constitutively expressed in neuronal cells in rat and human brain. The formation of larger amounts of alpha-OHALP in neurons points to local modulation of pharmacological activity in brain, at the site of action of the anti-anxiety drug. Since hydroxy metabolites of alprazolam are hydrophilic and not easily cleared through blood-CSF barrier, alpha-OHALP would potentially have a longer half-life in brain.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Alprazolam / metabolism*
  • Alprazolam / pharmacokinetics
  • Animals
  • Anti-Anxiety Agents / metabolism*
  • Anti-Anxiety Agents / pharmacokinetics
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Biotransformation
  • Blotting, Northern
  • Brain / enzymology*
  • Child
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • In Vitro Techniques
  • Liver / enzymology*
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Middle Aged
  • Organ Specificity
  • Rats
  • Rats, Wistar
  • Species Specificity


  • Anti-Anxiety Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cyp3a23-3a1 protein, rat
  • Cytochrome P-450 CYP3A
  • Alprazolam