¹Department of Neurochemistry, National Institute of Mental Health & Neurosciences, Bangalore, India

²National Brain Research Centre, ICGEB Campus, Aruna Asaf Ali Marg, New Delhi , India

Correspondence to: V Ravindranath, National Brain Research Centre, ICGEB Campus, Aruna Asaf Ali Marg, New Delhi - 110 067, India Tel: +91 124 630 8317 Fax: +91 124 622 0237 E-mail: vijir@vsnl.com

^aThese authors contributed equally to the work.

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

The Pharmacogenomics Journal (2002) 2, 243-258. doi:10.1038/sj.tpj.6500115

brain; drug metabolism; cytochrome P450; psychoactive drugs; monooxygenase; alprazolam