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

Pai, H. V. ; Upadhya, S. C. ; Chinta, S. J. ; Hegde, S. N. ; Ravindranath, V. (2002) Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite The Pharmacogenomics Journal, 2 . pp. 243-258. ISSN 1470-269X

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Official URL: http://www.nature.com/tpj/journal/v2/n4/abs/650011...

Related URL: http://dx.doi.org/10.1038/sj.tpj.6500115

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 α-hydroxy alprazolam (α-OHALP, pharmacologically more active). We examined P450 mediated metabolism of alprazolam by rat and human brain microsomes and observed that the relative amount of α-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 α-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, α-OHALP would potentially have a longer half-life in brain.

Item Type:Article
Source:Copyright of this article belongs to Nature Publishing Group.
Keywords:Brain; Drug Metabolism; Cytochrome P450; Psychoactive Drugs; Monooxygenase; Alprazolam
ID Code:40684
Deposited On:24 May 2011 13:54
Last Modified:17 May 2016 22:40

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