Samuelsson Kristin, Pickup Kathryn, Sarda Sunil, Swales John G, Morikawa Yoshio, Schulz-Utermoehl Timothy, Hutchison Michael, Wilson Ian D
Drug Metabolism and Pharmacokinetics IM, AstraZeneca UK Ltd., Alderley Park, Macclesfield, Cheshire, UK.
Xenobiotica. 2012 Nov;42(11):1128-37. doi: 10.3109/00498254.2012.689888. Epub 2012 May 30.
The pharmacokinetics and biotransformation of midazolam were investigated following single oral doses of 0.1, 1 and 10 mg/kg to chimeric mice with humanised livers (PXB mice) and to severe combined immunodeficient (SCID) mice used as controls. Pharmacokinetic analysis, on whole blood, revealed rapid absorption of the administered midazolam with a higher C(max) in PXB compared to SCID. The exposure to 1'-hydroxymidazolam was approximately 14-fold greater than to midazolam in the SCID mice and close to equivalent in the PXB mice. The metabolism of midazolam in SCID mice was faster than in the PXB mice such that pharmacokinetic data for midazolam in SCID mice could not be generated from the lowest dose in these animals. Both oxidative and conjugative metabolic pathways were identified in the PXB mice. All the major circulating metabolites observed in humans; 1'-hydroxymidazolam, 4'-hydroxymidazolam, 1',4'-dihydroxymidazolam and 1'-hydroxymidazolam glucuronide, were detected in the blood of PXB mice. However, 4'-hydroxymidazolam and the 1'-hydroxymidazolam glucuronide were not detected in blood samples obtained from SCID mice. The midazolam metabolite profile in the PXB mouse was similar to that previously reported for human suggesting that the PXB mouse model can provide a model system for predicting circulating human metabolites.
给具有人源化肝脏的嵌合小鼠（PXB小鼠）和用作对照的严重联合免疫缺陷（SCID）小鼠单次口服0.1、1和10mg/kg咪达唑仑后，研究了其药代动力学和生物转化。对全血进行的药代动力学分析显示，给予的咪达唑仑吸收迅速，与SCID小鼠相比，PXB小鼠的C(max)更高。在SCID小鼠中，1'-羟基咪达唑仑的暴露量比咪达唑仑大约高14倍，而在PXB小鼠中两者接近相当。SCID小鼠中咪达唑仑的代谢比PXB小鼠快，以至于无法从这些动物的最低剂量中得出SCID小鼠中咪达唑仑的药代动力学数据。在PXB小鼠中鉴定出了氧化和结合代谢途径。在PXB小鼠血液中检测到了在人类中观察到的所有主要循环代谢物；1'-羟基咪达唑仑、4'-羟基咪达唑仑、1',4'-二羟基咪达唑仑和1'-羟基咪达唑仑葡糖醛酸。然而，在从SCID小鼠获得的血样中未检测到4'-羟基咪达唑仑和1'-羟基咪达唑仑葡糖醛酸。PXB小鼠中的咪达唑仑代谢物谱与先前报道的人类相似，表明PXB小鼠模型可以提供一个预测循环人类代谢物的模型系统。
