Blanchard Nadège, Hewitt Nicola J, Silber Paul, Jones Hannah, Coassolo Philippe, Lavé Thierry
F. Hoffmann-La Roche AG, Pharmaceuticals Division, CH-4070 Basel, Switzerland.
J Pharm Pharmacol. 2006 May;58(5):633-41. doi: 10.1211/jpp.58.5.0008.
Cryopreserved human hepatocytes have been used to predict hepatic in-vivo clearance. Physiologically-based direct scaling methods generally underestimate human in-vivo hepatic clearance. Cryopreserved human hepatocytes were incubated in 100% serum and in serum-free medium to predict the in-vivo hepatic clearance of six compounds (phenazone (antipyrine), bosentan, mibefradil, midazolam, naloxone and oxazepam). Monte Carlo simulations were performed in an attempt to incorporate the variability and uncertainty in the measured parameters to the prediction of hepatic clearance. The intrinsic clearance (CL(int)) and the associated variability of the six compounds decreased in the presence of serum and the values were reproducible across donors. The predicted CL(hep, in-vivo) obtained with hepatocytes from donors incubated in serum was more accurate than the prediction obtained in the absence of serum. For example, the CL(hep, in-vivo) of mibefradil in donor GNG was 4.27 mL min(-1) kg(-1) in the presence of serum and 0.46 mL min(-1) kg(-1) in the absence of serum (4.88 mL min(-1) kg(-1) observed in-vivo). Using the results obtained in this study together with an extended data set (26 compounds), the clearance of 77% of the compounds was predicted within a 2-fold error in the absence of serum. In the presence of serum, 85% of the compounds were successfully predicted within a 2-fold error. In conclusion, cryopreserved human hepatocyte suspensions represented a convenient and predictive model to assess human drug clearance.
冷冻保存的人肝细胞已被用于预测肝脏的体内清除率。基于生理学的直接缩放方法通常会低估人体肝脏的体内清除率。将冷冻保存的人肝细胞在100%血清和无血清培养基中孵育，以预测六种化合物（非那宗（安替比林）、波生坦、米贝拉地尔、咪达唑仑、纳洛酮和奥沙西泮）的肝脏体内清除率。进行了蒙特卡罗模拟，试图将测量参数中的变异性和不确定性纳入肝脏清除率的预测中。六种化合物的内在清除率（CL(int)）及其相关变异性在血清存在下降低，并且这些值在不同供体之间具有可重复性。用在血清中孵育的供体肝细胞获得的预测CL(hep,体内)比在无血清情况下获得的预测更准确。例如，供体GNG中米贝拉地尔在有血清时的CL(hep,体内)为4.27 mL min(-1) kg(-1)，无血清时为0.46 mL min(-1) kg(-1)（体内观察值为4.88 mL min(-1) kg(-1)）。结合本研究获得的结果以及一个扩展数据集（26种化合物），在无血清情况下，77%的化合物清除率预测误差在2倍以内。在有血清的情况下，85%的化合物成功预测误差在2倍以内。总之，冷冻保存的人肝细胞悬液是评估人体药物清除率的一种方便且具有预测性的模型。
