Premium
Midazolam Hydroxylation by Human Liver Microsomes In Vitro : Inhibition by Fluoxetine, Norfluoxetine, and by Azole Antifungal Agents
Author(s) -
Moltke Lisa L.,
Greenblatt David J.,
Schmider Jürgen,
Duan Su Xiang,
Wright C. Eugene,
Harmatz Jerold S.,
Shader Richard I.
Publication year - 1996
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1996.tb04251.x
Subject(s) - ketoconazole , midazolam , metabolite , pharmacology , chemistry , azole , itraconazole , pharmacokinetics , microsome , fluoxetine , drug interaction , non competitive inhibition , in vivo , active metabolite , cytochrome p450 , cyp3a4 , in vitro , metabolism , biochemistry , enzyme , medicine , biology , serotonin , antifungal , receptor , microbiology and biotechnology , dermatology , sedation
Biotransformation of the imidazobenzodiazepine midazolam to its α‐hydroxy and 4‐hydroxy metabolites was studied in vitro using human liver microsomal preparations. Formation of α‐hydroxy‐midazolam was a high‐affinity (K m = 3.3 μmol/L) Michaelis‐Menten process coupled with substrate inhibition at high concentrations of midazolam. Formation of 4‐hydroxy‐midazolam had much lower apparent affinity (57 μmol/L), with minimal evidence of substrate inhibition. Based on comparison of V max /K m ratios for the two pathways, α‐hydroxy‐midazolam formation was estimated to account for 95% of net intrinsic clearance. Three azole antifungal agents were inhibitors of midazolam metabolism in vitro, with inhibition being largely consistent with a competitive mechanism. Mean competitive inhibition constants (K i ) versus α‐hydroxy‐midazolam formation were 0.0037 μmol/L for ketoconazole, 0.27 μmol/L for itraconazole, and 1.27 μmol/L for fluconazole. An in vitro‐in vivo scaling model predicted inhibition of oral midazolam clearance due to coadministration of ketoconazole or itraconazole; the predicted inhibition was consistent with observed interactions in clinical pharmacokinetic studies. The selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine and its principal metabolite, norfluoxetine, also were inhibitors of both pathways of midazolam biotransformation, with norfluoxetine being a much more potent inhibitor than was fluoxetine itself. This finding is consistent with results of other in vitro studies and of clinical studies, indicating that fluoxetine, largely via its metabolite norfluoxetine, may impair clearance of P450‐3A substrates .