Lucas M L, Swanston-Flatt S K, Blair J A
J Pharmacokinet Biopharm. 1982 Dec;10(6):615-35. doi: 10.1007/BF01062544.
When solute transfer through the intestinal in vitro everted sac preparation is described by a three-compartment system, solute transfer rate constants can be derived for the mucosal and serosal permeability barriers. A catenary variant has been presented as well as a mammillary one where paracellular movement of solute is additionally allowed for. The first order differential rate equations governing the change in solute concentration in all three compartments with respect to time have been solved and the explicit analytical solutions provided. Since these solutions are cumbersome to use in the estimation of the required rate constants, a least squares procedure has been applied directly to the differential form of the rate equations in order to derive the rate constants without recourse to the analytical solutions. Verification of the solutions and of the estimated rate constants was by substitution of the latter into the former to test the goodness of fit for folic acid absorption data. Both variants take into account the simultaneous fluid movement which occurs during absorption experiments and which complicates the interpretation of absorption data. The mammillary model showed that only 10% of folic acid movement could pass directly through the paracellular pathways and that the bulk of folate movement is probably through the epithelial cells. However the catenary model without paracellular movement gave just as good fit to the data and was used subsequently. Experiments investigating the effect of substances implicated in folate malabsorption were analyzed in terms of the catenary model for folic acid absorption, in order to investigate their effects on the transfer rate constants free from the complicating effects on fluid movement. When pronounced inhibition took place, as with methotrexate, the mucosal rate constants were reduced, whereas the serosal rate constants were elevated. Also, the forward (k12) mucosal rate constant correlated significantly with the overall folate transfer in contrast to the other rate constants. These observations are consonant with the concept of a mucosally sited entry step exerting a controlling influence over the transfer rate of folic acid rather than a serosally sited exit process and with the conclusion that this may be the site of action of substances causing folate malabsorption.
当通过三室系统描述溶质在体外肠外翻囊制备中的转运时，可推导出溶质在黏膜和浆膜通透性屏障的转运速率常数。提出了一种悬链线变体以及一种允许溶质进行细胞旁移动的乳头状模型。求解了描述所有三个隔室中溶质浓度随时间变化的一阶微分速率方程，并给出了显式解析解。由于这些解在估计所需速率常数时使用起来很麻烦，因此直接将最小二乘法应用于速率方程的微分形式，以便在不依赖解析解的情况下推导速率常数。通过将估计的速率常数代入解析解来检验拟合优度，从而对解析解和估计的速率常数进行验证，以测试对叶酸吸收数据的拟合情况。两种变体都考虑了吸收实验过程中同时发生的液体流动，而这种流动会使吸收数据的解释变得复杂。乳头状模型表明，只有10%的叶酸转运可以直接通过细胞旁途径，并且大部分叶酸转运可能是通过上皮细胞。然而，没有细胞旁移动的悬链线模型对数据的拟合同样良好，随后被采用。根据叶酸吸收的悬链线模型分析了研究与叶酸吸收不良有关的物质的影响的实验，以研究它们对转运速率常数的影响，而不受液体流动复杂影响的干扰。当出现明显抑制时，如甲氨蝶呤的情况，黏膜速率常数降低，而浆膜速率常数升高。此外，与其他速率常数相比，正向（k12）黏膜速率常数与总体叶酸转运显著相关。这些观察结果与以下概念一致，即黏膜部位的进入步骤对叶酸的转运速率施加控制影响，而不是浆膜部位的退出过程，并且得出结论，这可能是导致叶酸吸收不良的物质的作用位点。
