Björkman S, Wada D R, Stanski D R, Ebling W F
Hospital Pharmacy, Malmö General Hospital, Sweden.
J Pharmacokinet Biopharm. 1994 Oct;22(5):381-410. doi: 10.1007/BF02353862.
The objectives of this investigation were to characterize the disposition of fentanyl and alfentanil in 14 tissues in the rat, and to create physiological pharmacokinetic models for these opioids that would be scalable to man. We first created a parametric submodel for the disposition of either drug in each tissue and then assembled these submodels into whole-body models. The disposition of fentanyl and alfentanil in the heart and brain and of fentanyl in the lungs could be described by perfusion-limited 1-compartment models. The disposition of both opioids in all other examined tissues was characterized by 2- or 3-compartment models. From these models, the extraction ratios of the opioids in the various tissues could be calculated, confirming the generally lower extraction of alfentanil as compared to fentanyl. Assembly of the single-tissue models resulted in a wholebody model for fentanyl that accurately described its disposition in the rat. A similar assembly of the tissue models for alfentanil revealed non-first-order elimination kinetics that were not apparent in the blood concentration data. Michaelis-Menten parameters for the hepatic metabolism of alfentanil were determined by iterative optimization of the entire model. The parametric models were finally scaled to describe the disposition of fentanyl and alfentanil in humans.
本研究的目的是描述芬太尼和阿芬太尼在大鼠14种组织中的分布情况，并建立这些阿片类药物的生理药代动力学模型，使其能够按比例适用于人类。我们首先为每种药物在每个组织中的分布创建了一个参数子模型，然后将这些子模型组装成全身模型。芬太尼和阿芬太尼在心脏和大脑中的分布以及芬太尼在肺中的分布可用灌注限制的一室模型来描述。两种阿片类药物在所有其他检测组织中的分布可用二室或三室模型来表征。根据这些模型，可以计算出阿片类药物在各种组织中的提取率，证实与芬太尼相比，阿芬太尼的提取率通常较低。单组织模型的组装产生了一个芬太尼的全身模型，该模型准确地描述了其在大鼠体内的分布。阿芬太尼组织模型的类似组装显示出非一级消除动力学，这在血药浓度数据中并不明显。通过对整个模型进行迭代优化，确定了阿芬太尼肝脏代谢的米氏参数。最终对参数模型进行了缩放，以描述芬太尼和阿芬太尼在人体内的分布情况。
