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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 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.

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The authors thank Dr SK Shankar, for providing the human brain tissue through Human Brain Tissue Repository for Neurobiological Studies, Department of Neuropathology, NIMHANS and Dr FP Guengerich for antiserum to P4503A4 and Dr NG Avadhani for providing the cDNA to CYP3A1. The technical assistance of Mr VK Prasanna is acknowledged. This research was supported by National Institutes of Health grant MH55494.

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Correspondence to V Ravindranath.

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Pai, H., Upadhya, S., Chinta, S. et al. Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite. Pharmacogenomics J 2, 243–258 (2002).

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