Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia.
Eur J Clin Pharmacol. 2010 Mar;66(3):275-83. doi: 10.1007/s00228-009-0760-2. Epub 2009 Dec 11.
To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitro-in vivo extrapolation; IV-IVE).
A co- vs. pre-incubation strategy was used to quantify time-dependent inhibition of human liver microsomal (HLM) and recombinant CYP3A4 (rCYP3A4) by zolpidem. Experiments involving a 10-fold dilution step were employed to determine the kinetic constants of inactivation (K (I) and k (inact)) and to assess the in vitro mechanism-based inactivation (MBI) criteria. Inactivation data were entered into the Simcyp population-based ADME simulator to predict the increase in the area under the plasma concentration-time curve (AUC) for orally administered midazolam.
Consistent with MBI, the inhibitory potency of zolpidem toward CYP3A was increased following pre-incubation. In HLMs, the concentration required for half maximal inactivation (K (I)) was 122 microM and the maximal rate of inactivation (k (inact)) was 0.094 min(-1). In comparison, K (I) and k (inact) values with rCYP3A4 were 50 microM and 0.229 min(-1), respectively. Zolpidem fulfilled all other in vitro MBI criteria, including irreversible inhibition. The mean oral AUC for midazolam in healthy volunteers was predicted to increase 1.1- to 1.7-fold due to the inhibition of metabolic clearance by zolpidem. Elderly subjects were more sensitive to the interaction, with mean increases in midazolam AUC of 1.2- and 2.2-fold for HLM IV-IVE and rCYP3A4 IV-IVE, respectively.
Zolpidem is a relatively weak mechanism-based inactivator of human CYP3A in vitro. Zolpidem is unlikely to act as a significant perpetrator of metabolic interactions involving CYP3A.
评估唑吡坦作为人细胞色素 CYP3A 的一种基于机制的体外失活剂，并评估其与 CYP3A 药物的代谢相互作用潜力（体外-体内外推法；IV-IVE）。
采用共孵育与预孵育策略来量化唑吡坦对人肝微粒体（HLM）和重组 CYP3A4（rCYP3A4）的时间依赖性抑制作用。采用 10 倍稀释步骤进行实验，以确定失活的动力学常数（K（I）和 k（inact））并评估体外基于机制的失活（MBI）标准。失活数据输入到 Simcyp 基于人群的 ADME 模拟器中，以预测口服咪达唑仑的血浆浓度-时间曲线下面积（AUC）增加。
与 MBI 一致，唑吡坦对 CYP3A 的抑制效力在预孵育后增加。在 HLMs 中，半数最大失活浓度（K（I））为 122μM，最大失活速率（k（inact））为 0.094min（-1）。相比之下，rCYP3A4 的 K（I）和 k（inact）值分别为 50μM 和 0.229min（-1）。唑吡坦满足所有其他体外 MBI 标准，包括不可逆抑制。预计健康志愿者口服咪达唑仑的 AUC 平均增加 1.1-1.7 倍，因为唑吡坦抑制了代谢清除率。老年受试者对相互作用更为敏感，HLM-IV-IVE 和 rCYP3A4-IV-IVE 中咪达唑仑 AUC 的平均增加分别为 1.2-和 2.2 倍。
唑吡坦在体外是一种相对较弱的人细胞色素 CYP3A 的基于机制的失活剂。唑吡坦不太可能成为涉及 CYP3A 的代谢相互作用的重要促成因素。
