Inhibitors of alprazolam metabolism in vitro: effect of serotonin‐ reuptake‐inhibitor antidepressants, ketoconazole and quinidine.

Abstract

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). 1994 The British Pharmacological Society