Mikus Gerd, Heinrich Tilman, Bödigheimer Julia, Röder Claudia, Matthee Anne-Kathrin, Weiss Johanna, Burhenne Jürgen, Haefeli Walter E
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
J Clin Pharmacol. 2017 Jul;57(7):899-905. doi: 10.1002/jcph.879. Epub 2017 Feb 14.
This study aimed to assess whether a single oral dose of the nonnucleoside reverse transcriptase inhibitor efavirenz can alter CYP3A in vivo. In 12 healthy participants individual CYP3A activity was quantified using a semisimultaneous methodology (midazolam orally and 6 hours later intravenously) both alone and during a period of 22 days after a single oral dose of 400 mg efavirenz. Twelve hours after efavirenz administration, midazolam apparent oral clearance was significantly increased by 70%, and midazolam systemic clearance after intravenous administration was significantly increased by 27%. Similar effects were still present on day 6, after which midazolam clearances slowly returned to baseline on day 22. At least on day 1, the midazolam clearance increase is consistent with the in vitro observed CYP3A activation. The onset of an efavirenz treatment will almost immediately result in enhanced elimination of CYP3A substrates.
本研究旨在评估单次口服非核苷类逆转录酶抑制剂依非韦伦是否能在体内改变细胞色素P450 3A（CYP3A）。在12名健康受试者中，采用半同步方法（口服咪达唑仑，6小时后静脉注射）分别单独测定以及在单次口服400 mg依非韦伦后的22天内测定个体CYP3A活性。依非韦伦给药12小时后，咪达唑仑的表观口服清除率显著增加70%，静脉注射后咪达唑仑的全身清除率显著增加27%。在第6天仍存在类似效应，之后在第22天咪达唑仑清除率缓慢恢复至基线水平。至少在第1天，咪达唑仑清除率的增加与体外观察到的CYP3A激活一致。依非韦伦治疗开始后几乎会立即导致CYP3A底物的清除增强。
