Differential Metabolism of Alprazolam by Liver and Brain Cytochrome (P4503A) to Pharmacologically Active Metabolite
The Pharmacogenomics Journal (2002) 2, 243–258 2002 Nature Publishing Group All rights reserved 1470-269X/02 $25.00 www.nature.com/tpj ORIGINAL ARTICLE Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite HV Pai1,2* ABSTRACT SC Upadhya1,2* Cytochrome P450 (P450) is a superfamily of enzymes which mediates metab- 1 olism of xenobiotics including drugs. Alprazolam, an anti-anxiety agent, is SJ Chinta * metabolized in rat and human liver by P4503A1 and P4503A4 respectively, SN Hegde1 to 4-hydroxy alprazolam (4-OHALP, pharmacologically less active) and ␣- V Ravindranath1,2 hydroxy alprazolam (␣-OHALP, pharmacologically more active). We exam- ined P450 mediated metabolism of alprazolam by rat and human brain 1Department of Neurochemistry, National microsomes and observed that the relative amount of ␣-OHALP formed in Institute of Mental Health & Neurosciences, brain was higher than liver. This biotransformation was mediated by a P450 Bangalore, India; 2National Brain Research Centre, ICGEB Campus, Aruna Asaf Ali Marg, isoform belonging to P4503A subfamily, which is constitutively expressed in New Delhi , India neuronal cells in rat and human brain. The formation of larger amounts of ␣-OHALP in neurons points to local modulation of pharmacological activity Correspondence: in brain, at the site of action of the anti-anxiety drug. Since hydroxy metab- V Ravindranath, National Brain Research olites of alprazolam are hydrophilic and not easily cleared through blood- Centre, ICGEB Campus, Aruna Asaf Ali ␣ Marg, New Delhi - 110 067, India CSF barrier, -OHALP would potentially have a longer half-life in brain. Tel: +91 124 630 8317 The Pharmacogenomics Journal (2002) 2, 243–258.
[Show full text]