Drug interaction of efavirenz and midazolam

• Verfasst von: Keubler, Anja [VerfasserIn]
• Verfasst von: Weiß, Johanna [VerfasserIn]
• Verfasst von: Haefeli, Walter E. [VerfasserIn]
• Verfasst von: Mikus, Gerd [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Titel: Drug interaction of efavirenz and midazolam
• Titelzusatz: efavirenz activates the CYP3A-mediated midazolam 1′-Hydroxylation in vitro
• Verf.angabe: Anja Keubler, Johanna Weiss, Walter E. Haefeli, Gerd Mikus, Jürgen Burhenne
• E-Jahr: 2012
• Jahr: May 16, 2012
• Umfang: 5 S.
• Fussnoten: Published online May 16, 2012 ; Gesehen am 14.08.2018
• Titel Quelle: Enthalten in: Drug metabolism and disposition
• Ort Quelle: Bethesda, Md. : ASPET, 1973
• Jahr Quelle: 2012
• Band/Heft Quelle: 40(2012), 6, Seite 1178-1182
• ISSN Quelle: 1521-009X
• DOI: doi:10.1124/dmd.111.043844
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1579234925

Abstract

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.