Department of PK Sciences, ADME Section, Novartis Institutes for BioMedical Research, Basel, Switzerland; Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland.
Department of PK Sciences, ADME Section, Novartis Institutes for BioMedical Research, Basel, Switzerland.
J Pharm Sci. 2017 Sep;106(9):2805-2814. doi: 10.1016/j.xphs.2017.03.025. Epub 2017 Apr 4.
Unbound intrahepatic drug concentrations determine the interaction potential with intracellular targets related to toxicity, pharmacokinetics, or pharmacodynamics. Recently, the unbound liver-to-blood partition coefficient (Kp) based on the Extended Clearance Model (ECM) has been developed providing indirect estimates of unbound intrahepatic drug concentrations. This study aimed to determine Kp for 18 diverse drug compounds by 3 alternative in vitro methods and to compare the outcome with the ECM approach. Kp was calculated from independent measurements of hepatocellular drug accumulation (Kp) and unbound fraction in hepatocytes (fu) either assessed from steady-state accumulation at 4°C (temperature method), using equilibrium dialysis (homogenization method), or empirically from logD (logD method). Deviations to ECM-based Kp data were closely linked to the absence of intrinsic clearance processes (metabolism, biliary secretion) in the investigated methods. Differences in fu additionally contributed to deviations in Kp. The homogenization method generally provided lowest fu values, especially for compounds with high molecular weight or low logD. Kp values of compounds with low intrinsic clearance correlated well between the ECM and temperature methods independent of physicochemical properties. Therefore, only the ECM provides an integrated quantitative determination of hepatic Kp. Temperature and homogenization methods, however, represent useful alternatives if compound properties are appropriately considered.
未结合的肝内药物浓度决定了与毒性、药代动力学或药效动力学相关的细胞内靶点的相互作用潜力。最近，基于扩展清除模型 (ECM) 的未结合肝-血分配系数 (Kp) 已经被开发出来，提供了未结合肝内药物浓度的间接估计。本研究旨在通过 3 种替代的体外方法确定 18 种不同药物化合物的 Kp，并将结果与 ECM 方法进行比较。Kp 是从肝细胞中药物蓄积的独立测量值 (Kp) 和未结合分数 (fu) 计算得出的，这些测量值可以通过 4°C 时的稳态蓄积来评估 (温度法)，也可以通过平衡透析 (匀浆法) 或经验从 logD (logD 法) 来评估。与 ECM 方法得出的 Kp 值相比，偏差与研究方法中缺乏内在清除过程 (代谢、胆汁分泌) 密切相关。fu 的差异也导致了 Kp 的偏差。匀浆法通常提供最低的 fu 值，尤其是对于分子量高或 logD 值低的化合物。与理化性质无关，具有低内在清除率的化合物的 Kp 值在 ECM 和温度方法之间相关性良好。因此，只有 ECM 提供了肝 Kp 的综合定量测定。然而，如果适当考虑化合物的性质，温度和匀浆法是有用的替代方法。
