Yang Qi Joy, Fan Jianghong, Chen Shu, Liu Lutan, Sun Huadong, Pang K Sandy
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Drug Metab Dispos. 2016 Jul;44(7):1123-38. doi: 10.1124/dmd.116.069542. Epub 2016 Apr 20.
We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3β-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in vivo. The SFM model describes a partial (5%-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region, whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG crossing the liver or intestinal basolateral membranes mandates that most of MG that is excreted into bile is hepatically formed, whereas MG that is excreted into urine originates from both intestine and liver metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile [Formula: see text] for intraduodenal/intravenous dosing is expected to exceed unity for the SFM but approximates unity for the TM. Compartmental analysis of morphine and MG data, without consideration of the permeability of MG and where MG is formed, suggests the ratio to be 1 and failed to describe the kinetics of MG. The observed intraduodenal/intravenous ratio of [Formula: see text] (2.55 at 4 hours) was better predicted by the SFM-PBPK (2.59 at 4 hours) and not the TM-PBPK (1.0), supporting the view that the SFM is superior for the description of intestinal-liver metabolism of morphine to MG. The SFM-PBPK model predicts an appreciable contribution of the intestine to first pass M metabolism.
我们使用肠道分离流模型（SFM）与传统模型（TM），将其嵌套在基于生理学的药代动力学（PBPK）模型中，以描述大鼠体内静脉注射和十二指肠内给药吗啡后吗啡3β-葡萄糖醛酸苷（MG）的胆汁和尿液排泄情况。SFM模型描述了部分（5%-30%）的肠道血流灌注富含转运体和酶的肠上皮细胞区域，而TM模型描述的是100%的血流灌注整个肠道。对于SFM模型，由于分离流的存在，从循环中进入的药物预计在肠道中代谢程度较低，这反映了分流和肠道代谢的途径依赖性现象。MG穿过肝或肠基底外侧膜的通透性较差，这意味着排入胆汁的大部分MG是在肝脏中形成的，而排入尿液的MG则来自肠道和肝脏的代谢，因为MG会回流到血液中。十二指肠内/静脉给药时，尿液/胆汁中MG的量之比[公式：见正文]预计SFM模型会超过1，而TM模型接近1。在不考虑MG的通透性和MG形成位置的情况下，对吗啡和MG数据进行房室分析，结果表明该比值为1，无法描述MG的动力学。观察到的十二指肠内/静脉给药比值[公式：见正文]（4小时时为2.55），SFM-PBPK模型预测效果更好（4小时时为2.59），而TM-PBPK模型预测效果不佳（1.0），这支持了SFM模型在描述吗啡向MG的肠肝代谢方面更具优势的观点。SFM-PBPK模型预测肠道对首过M代谢有显著贡献。
