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PMID: 7946933 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

British journal of clinical pharmacology ·Vol. 38 ·No. 1 ·1994-07-00 ·Pages 23-31

von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Harmatz JS, Shader RI

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).

MeSH Terms
Adult Aged Alprazolam/metabolism,pharmacokinetics Animals Antidepressive Agents/pharmacology Biotransformation Female Humans Hydroxylation Ketoconazole/pharmacology Macaca fascicularis Male Mice Microsomes, Liver/drug effects,metabolism Middle Aged Quinidine/pharmacology Rats Rats, Sprague-Dawley Serotonin Uptake Inhibitors/pharmacology Species Specificity
Chemicals
Antidepressive Agents Serotonin Uptake Inhibitors Quinidine Ketoconazole Alprazolam
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
von Moltke L L
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111.
Greenblatt D J
Cotreau-Bibbo M M
Harmatz J S
Shader R I
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Article Info
Journal
British journal of clinical pharmacology
Abbr.
Br J Clin Pharmacol
ISSN
0306-5251
DOI
10.1111/j.1365-2125.1994.tb04317.x
Published
1994-07-00
Pages
23-31
Language
English
Region
England
NLM ID
7503323
PMCID
PMC1364833
Subset
IM
Grants
NIMH NIH HHS · MH-34223 · United States
External Links
PubMed source DOI: 10.1111/j.1365-2125.1994.tb04317.x PMC Full Text View journal details
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