Use of Micropatterned Cocultures to Detect Compounds That Cause Drug-Induced Liver Injury in Humans
Use of Micropatterned Cocultures to Detect Compounds That Cause Drug-Induced Liver Injury in Humans
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DOI：
10.1093/toxsci/kfs326
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发表时间：
2013-03-01
影响因子：
3.8
通讯作者：
Will, Yvonne
中科院分区：
文献类型：
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作者：
Khetani, Salman R.;Kanchagar, Chitra;Will, Yvonne
由于药物诱导的肝损伤（DILI）仍然是晚期药物消耗的主要原因，因此需要可在整个药物发现过程中部署的预测性测定。使用体外培养的原代人肝细胞的24小时培养物和四个细胞损伤终点的成像，可以以类似于50%的灵敏度和类似于5%的假阳性（FP）率预测临床DILI（Xu et al.，2008年）。我们假设在功能稳定的原代肝细胞模型（微模式共培养物[MPCCs]）中长期给药可以提供比短期给药模式更高的预测性。我们使用原代人或大鼠肝细胞的MPC来了解可能的种属差异沿着标准终点（谷胱甘肽水平、ATP水平、白蛋白和尿素分泌），以检测已知或未知引起临床DILI的45种药物。人MPC正确检测到已知引起DILI的35种化合物中的23种（灵敏度为65.7%），10种阴性化合物的FP率为10%。大鼠MPCCs正确检测了35种DILI化合物中的17种（灵敏度为48.6%），FP率高于人MPCCs（20 vs. 10%）。对于另外19种最受DILI关注的药物，当使用至少两个肝细胞供体进行检测时，人MPC显示出100%的灵敏度。此外，MPCC能够检测结构药物类似物的相对临床毒性。总之，MPC显示出优于传统短期培养的临床DILI预测，和人类MPC更预测人类负债比他们的大鼠同行。
Because drug-induced liver injury (DILI) remains a major reason for late-stage drug attrition, predictive assays are needed that can be deployed throughout the drug discovery process. Clinical DILI can be predicted with a sensitivity of similar to 50% and a false positive (FP) rate of similar to 5% using 24-h cultures of sandwich-cultured primary human hepatocytes and imaging of four cell injury endpoints (Xu et al., 2008). We hypothesized that long-term drug dosing in a functionally stable model of primary hepatocytes (micropatterned cocultures [MPCCs]) could provide for increased predictivity over short-term dosing paradigms. We used MPCCs with either primary human or rat hepatocytes to understand possible species differences along with standard endpoints (glutathione levels, ATP levels, albumin, and urea secretion) to test 45 drugs either known or not known to cause clinical DILI. Human MPCCs correctly detected 23 of 35 compounds known to cause DILI (65.7% sensitivity), with a FP rate of 10% for the 10 negative compounds tested. Rat MPCCs correctly detected 17 of 35 DILI compounds (48.6% sensitivity) and had a higher FP rate than human MPCCs (20 vs. 10%). For an additional 19 drugs with the most DILI concern, human MPCCs displayed a sensitivity of 100% when at least two hepatocyte donors were used for testing. Furthermore, MPCCs were able to detect relative clinical toxicities of structural drug analogs. In conclusion, MPCCs showed superiority over conventional short-term cultures for predictions of clinical DILI, and human MPCCs were more predictive for human liabilities than their rat counterparts.