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Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants

Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants

  1. Jatelka
    British Journal of Clinical Pharmacology 1994 Jul;38(1):23-31

    von Moltke LL (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Greenblatt DJ (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Cotreau-Bibbo MM (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Harmatz JS (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Shader RI (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).

    1. The biotransformation of the triazolobenzodiazepine alprazolam (ALP) to its hydroxylated metabolites (4-OH-ALP and alpha-OH-ALP) was evaluated in human, monkey, rat, and mouse liver microsomes.

    2. In all species 4-OH-ALP was the principal metabolite, accounting for 84% of clearance in human microsomes compared with 16% for alpha-OH-ALP.

    3. Among the serotonin-specific reuptake inhibitors fluoxetine (FLU) and sertraline (SERT), and their respective demethylated metabolites norfluoxetine (NOR) and desmethylsertraline (DES), NOR was the most potent inhibitor (mean Ki for 4-OH-ALP formation in humans: 11 microM), FLU the weakest (Ki = 83 microM), with SERT and DES falling in between (Ki = 24 and 20 microM).

    4. The in vitro data predict 29% inhibition of ALP clearance at mean FLU and NOR plasma concentrations of 77 ng ml-1 and 72 ng ml-1, respectively, after correction for liver:water partition ratios in the range of 12-14. The observed mean degree of inhibition in a previous in vivo study was 21%. 5. Ketoconazole was a potent inhibitor of ALP metabolism in vitro (Ki = 0.046 microM), suggesting that ALP hydroxylation is mediated by the cytochrome P450-3A sub-family. Quinidine was a weak inhibitor (Ki = 626 microM).