In vivo studies have shown cyclic bile salt (BS) outputs during fasting whereas higher amounts have been observed in fed states. This leads to fluctuations of intestinal BS concentrations ([BS]) that can affect the rate and extent of absorption of lipophilic drugs in particular. However, most PBPK models use fixed values of [BS] in fasted and fed states albeit with different values in different regions of the GI tract. During fasting, there is a relationship between gallbladder volume (GBV) and the phase of the Interdigestive Migrating Motor Complex cycle (IMMCc), showing cyclic GBV changes with periodic filling and emptying. This relationship is also affected by the origin of the IMMCc (antral or duodenal). In fed states, meta-analysis indicated that GB residual volume (% of fasting maximum) was 46.4 ± 27%CV and 30.7 ± 48%CV for low- and high-fat meals, respectively. The corresponding values for the duration of the emptying phase were for low fat meals 0.72h ± 1%CV and for high fat meals 1.17h ± 37%CV. The model, the Advanced Dynamic Bile Salt Model (ADBSM), was built bottom-up and its parameters were not fitted against in vivo measurements of [BS]. It involved update of the dynamic luminal fluid volumes model based on meta-analysis of available imaging data. The ADBSM is incorporated into the Simcyp (v18r2) PBPK simulator. The model predictivity was good (within 1.25-fold error for 11/20 of the clinical studies) and was assessed against clinical studies of luminal [BS] that provide only the type of meal (i.e., low- or high-fat), the timing of the meal and/or water intake events, and the number and age range of the study participants. The model is also an important component of models capturing enterohepatic recirculation of drug and metabolite. Further work is required to validate the current model and compare to simpler models with respect to drug absorption, especially of the lipophilic compounds.

中文翻译：

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基于人群的PBPK模型用于预测GI发光液中随时间变化的胆汁盐的分布。

体内研究表明，禁食期间可产生胆汁盐（BS），而在进食状态下可观察到更高的含量。这会导致肠道BS浓度（[BS]）的波动，特别是会影响亲脂性药物吸收的速率和程度。但是，大多数PBPK模型在禁食和进食状态下都使用[BS]的固定值，尽管在胃肠道的不同区域具有不同的值。禁食期间，胆囊容量（GBV）与消化间迁移运动复合体周期（IMMCc）的相位之间存在关系，表明周期性GBV随周期性填充和排空而变化。这种关系也受IMMCc（肛门或十二指肠）起源的影响。在进食状态下，荟萃分析表明，GB残留量（最大空腹百分比）为46.4±27％CV和30。低脂餐和高脂餐的CV分别为7±48％。排空阶段持续时间的相应值分别为低脂餐0.72h±1％CV和高脂餐1.17h±37％CV。该模型是自底向上构建的高级动态胆汁盐模型（ADBSM），其参数与[BS]的体内测量值不符。它涉及基于可用成像数据的荟萃分析来更新动态腔液量模型。ADBSM已合并到Simcyp（v18r2）PBPK仿真器中。模型的预测性很好（临床研究的11/20的误差在1.25倍之内），并根据仅提供膳食类型（即低脂或高脂），进餐和/或饮水事件的时间安排，以及研究参与者的数量和年龄范围。该模型还是捕获药物和代谢产物的肝肠循环的模型的重要组成部分。需要进一步的工作来验证当前模型并就药物尤其是亲脂性化合物的药物吸收与更简单的模型进行比较。