Brill M J E, Välitalo P A J, Darwich A S, van Ramshorst B, van Dongen H P A, Rostami-Hodjegan A, Danhof M, Knibbe C A J
Division of Pharmacology Leiden Academic Centre for Drug Research, Leiden University Leiden The Netherlands; Department of Clinical Pharmacy St. Antonius Hospital Nieuwegein The Netherlands.
Division of Pharmacology Leiden Academic Centre for Drug Research, Leiden University Leiden The Netherlands.
CPT Pharmacometrics Syst Pharmacol. 2016 Jan;5(1):20-30. doi: 10.1002/psp4.12048. Epub 2015 Dec 18.
This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi-PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40-1.64) times higher compared to morbidly obese patients before surgery (P < 0.01). Midazolam gut wall clearance (CLint,G) was slightly lower in patients after surgery (P > 0.05), with low values for both groups. The results of the semi-PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.
本研究旨在描述接受口服和静脉注射咪达唑仑的病态肥胖患者在减肥手术前（n = 20）和减肥手术后一年（n = 18）时咪达唑仑及其细胞色素P450 3A（CYP3A）介导的代谢产物1-羟基咪达唑仑的药代动力学，从而深入了解减肥手术对肠壁和肝脏中CYP3A活性的影响。在一个评估了不同血流情况的基于半生理学的药代动力学（半PBPK）模型中，与术前病态肥胖患者相比，咪达唑仑的肝内在清除率（CLint，H）高出2倍（95%置信区间1.40 - 1.64）（P < 0.01）。术后患者的咪达唑仑肠壁清除率（CLint，G）略低（P > 0.05），两组的值都较低。半PBPK模型的结果表明，与病态肥胖患者相比，减肥手术后患者的CYP3A肝脏代谢能力似乎有所恢复，而CYP3A介导的CLint，G在这两个人群中都较低，并且个体间差异较大。
