Abstract
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
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Alprazolam / metabolism*
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Alprazolam / pharmacokinetics
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Animals
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Anti-Anxiety Agents / metabolism*
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Anti-Anxiety Agents / pharmacokinetics
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
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Aryl Hydrocarbon Hydroxylases / metabolism*
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Biotransformation
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Blotting, Northern
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Brain / enzymology*
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Child
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism*
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Enzyme Inhibitors / pharmacology
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Female
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Fluorescent Antibody Technique
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Humans
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Immunohistochemistry
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In Situ Hybridization, Fluorescence
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In Vitro Techniques
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Liver / enzymology*
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Male
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Middle Aged
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Organ Specificity
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Rats
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Rats, Wistar
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Species Specificity
Substances
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Anti-Anxiety Agents
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Cytochrome P-450 Enzyme Inhibitors
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Enzyme Inhibitors
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Cytochrome P-450 Enzyme System
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Aryl Hydrocarbon Hydroxylases
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CYP3A protein, human
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Cyp3a23-3a1 protein, rat
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Cytochrome P-450 CYP3A
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Alprazolam