Horkovics-Kovats Stefan, Zlatos Pavol
Clinical Development, Sandoz GmbH, A-6250 Kundl, Austria.
Math Biosci. 2006 Sep;203(1):19-36. doi: 10.1016/j.mbs.2006.02.001. Epub 2006 Apr 17.
A 17-compartment linear pharmacokinetic model is designed, describing the complex process of enterohepatic circulation as a superposition of the net (remetabolizationfree) enterohepatic circulation, and remetabolization with subsequent intestinal absorption of the parent drug. Basically, the model is built by doubling the model describing the circulation of the parent drug in the body, so that the remetabolizable metabolite circulates in a model of the same structure as does the parent compound. The two submodels are cross-connected with arrows denoting the transition of the particular substance into the complementary part of the complex model. Asymptotic properties of the model are investigated, in particular, explicit formulas for its pharmacokinetic endpoints are given using the elements of its transition probability matrix. Conversely, taking account of the effect of bile cannulation, intravenous, intraportal and oral administration of the drug, as well as of the intravenous and intraportal administration of the remetabolizable metabolite, the transition probabilities of the system are determined in terms of certain measurable pharmacokinetic endpoints and the flow rates through the kidneys, liver and the cardiac output. Finally, the influence of the enterohepatic circulation and remetabolization process on bioavailability is examined. In particular, the inclusion-exclusion formula is derived, expressing its joint efficiency (defined as the relative increase of bioavailability) by means of the efficiencies of the net enterohepatic circulation and of the remetabolization process.
设计了一个17室线性药代动力学模型，将肠肝循环的复杂过程描述为净（无再代谢）肠肝循环与母体药物随后经肠道吸收的再代谢的叠加。基本上，该模型是通过将描述母体药物在体内循环的模型加倍构建而成的，这样可再代谢的代谢物就在与母体化合物相同结构的模型中循环。这两个子模型通过箭头交叉连接，箭头表示特定物质向复杂模型的互补部分的转变。研究了该模型的渐近性质，特别是利用其转移概率矩阵的元素给出了其药代动力学终点的显式公式。相反，考虑到胆管插管、药物的静脉内、门静脉内和口服给药以及可再代谢代谢物的静脉内和门静脉内给药的影响，根据某些可测量的药代动力学终点以及通过肾脏、肝脏的流量和心输出量来确定系统的转移概率。最后，研究了肠肝循环和再代谢过程对生物利用度的影响。特别是，推导了包含-排除公式，通过净肠肝循环和再代谢过程的效率来表示其联合效率（定义为生物利用度的相对增加）。
