Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite.
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.
Department of Neurochemistry, National Institute of Mental Health & Neurosciences, Bangalore, India.
H V
HV
Pai
S C
SC
Upadhya
S J
SJ
Chinta
S N
SN
Hegde
V
V
Ravindranath
D000328:Adult; D000368:Aged; D000525:Alprazolam / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001711:Biotransformation; D015152:Blotting, Northern; D001921:Brain / Q000201:enzymology*; D002648:Child; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D014151:Anti-Anxiety Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D000525:Alprazolam