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6396113 
Journal Article 
Clearance prediction methodology needs fundamental improvement: trends common to rat and human hepatocytes/microsomes and implications for experimental methodology 
Wood, FL; Houston, JB; Hallifax, D 
2017 
Yes 
Drug Metabolism and Disposition
ISSN: 0090-9556
EISSN: 1521-009X 
45 
11 
1178-1188 
English 
28887366 
WOS:000414243100004 
has erratum 6396114 Correction to ""
Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role in drug discovery, it is widely acknowledged that reliably accurate prediction is not yet achievable despite the predominance of hepatically cleared drugs. Physiologically mechanistic methodology tends to underpredict clearance by several fold, and empirical correction of this bias is confounded by imprecision across drugs. Understanding the causes of prediction uncertainty has been slow, possibly reflecting poor resolution of variables associated with donor source and experimental methods, particularly for the human situation. It has been reported that among published human hepatocyte predictions there was a tendency for underprediction to increase with increasing in vivo intrinsic clearance, suggesting an inherent limitation using this particular system. This implied an artifactual rate limitation in vitro, although preparative effects on cell stability and performance were not yet resolved from assay design limitations. Here, to resolve these issues further, we present an up-to-date and comprehensive examination of predictions from published rat as well as human studies (where n = 128 and 101 hepatocytes and n = 71 and 83 microsomes, respectively) to assess system performance more independently. We report a clear trend of increasing underprediction with increasing in vivo intrinsic clearance, which is similar both between species and between in vitro systems. Hence, prior concerns arising specifically from human in vitro systems may be unfounded and the focus of investigation in the future should be to minimize the potential in vitro assay limitations common to whole cells and subcellular fractions. 
IRIS
• Chloroprene