Drug interaction of efavirenz and midazolam: efavirenz activates the CYP3A-mediated midazolam 1′-Hydroxylation in vitro
CYP3A4 and CYP3A5 are the most important drug-metabolizing enzymes. For several drugs, heteroactivation of CYP3A-mediated reactions has been demonstrated in vitro. In vivo data suggested a possible acute activation of CYP3A4-catalyzed midazolam metabolism by efavirenz. Therefore, we aimed to investi...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
May 16, 2012
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| In: |
Drug metabolism and disposition
Year: 2012, Jahrgang: 40, Heft: 6, Pages: 1178-1182 |
| ISSN: | 1521-009X |
| DOI: | 10.1124/dmd.111.043844 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1124/dmd.111.043844 Verlag, Volltext: http://dmd.aspetjournals.org/content/40/6/1178 
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| Verfasserangaben: | Anja Keubler, Johanna Weiss, Walter E. Haefeli, Gerd Mikus, Jürgen Burhenne |
MARC
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| 245 | 1 | 0 | |a Drug interaction of efavirenz and midazolam |b efavirenz activates the CYP3A-mediated midazolam 1′-Hydroxylation in vitro |c Anja Keubler, Johanna Weiss, Walter E. Haefeli, Gerd Mikus, Jürgen Burhenne |
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| 520 | |a CYP3A4 and CYP3A5 are the most important drug-metabolizing enzymes. For several drugs, heteroactivation of CYP3A-mediated reactions has been demonstrated in vitro. In vivo data suggested a possible acute activation of CYP3A4-catalyzed midazolam metabolism by efavirenz. Therefore, we aimed to investigate the effect of efavirenz on the in vitro metabolism of midazolam. The formation of 1′-hydroxymidazolam was studied in pooled human liver microsomes (HLM) and recombinant human CYP3A4 and CYP3A5 (rCYP3A4 and rCYP3A5) in the presence of efavirenz (0.5, 1, and 5 μM). Product formation rates (Vmax) increased with increasing efavirenz concentrations (∼1.5-fold increase at 5 μM efavirenz in HLM and ∼1.4-fold in rCYP3A4). The activation in rCYP3A4 was dependent on cytochrome b5, and the activating effect was also observed in rCYP3A5 supplemented with cytochrome b5, where Vmax was ∼1.3-fold enhanced. Concomitant inhibition of CYP3A activity with ketoconazole in HLM abolished the increase in the 1′-hydroxymidazolam formation rate, further confirming involvement of CYP3A. The results of this study represent a distinct acute activation of midazolam metabolism and support the in vivo observations. Moreover, only efavirenz, but not its major metabolite 8-hydroxyefavirenz, was responsible for the activation. The increase in 1′-hydroxymidazolam formation may have been caused by binding of efavirenz to a peripheral site of the enzyme, leading to enhanced midazolam turnover due to changes at the active site. | ||
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