title: Prediction of hepatic plasma clearance in vivo from gel-entrapped rat and human hepatocytes.
abstract: This paper aimed to evaluate the applicability of gel-entrapped rat and human hepatocytes in the prediction of hepatic plasma clearance (CLh,plasma) in vivo. The in vitro intrinsic clearances (CLint,in vitro) for the selected compounds were determined from the substrate disappearance rate, and further used to predict CLh,plasma using 3 classical mathematical models (well-stirred, parallel-tube, and dispersion) and disregarding drug binding. As a result, the predicted values from gel-entrapped rat hepatocytes were mostly within 2 SE of the literature data with a high correlation coefficient (R(2)) of 0.88-0.91. The predicted data with human hepatocytes also fitted well with the clinical data, indicating a high accuracy in prediction of in-vivo clearance. With respect to the mathematical model for predicting CLh,plasma, the parallel-tube and dispersion models produced a better prediction than the well-stirred model, and we suggest using the parallel-tube model because it is less complex mathematically. In conclusion, gel-entrapped hepatocytes predicted the drug clearance well and seemed to be a useful tool in the process of drug discovery.
authors: Department of Chemical and Biochemical Engineering, Zhejiang University, 38 Zheda Road, Zhejiang 310027, PR China.
authors: Jian
authors: J
authors: Yin
authors: Hongxia
authors: H
authors: Qiu
authors: Jing
authors: J
authors: Dai
authors: Yanhua
authors: Y
authors: Lu
authors: Rong
authors: R
authors: Zhao
authors: Li
authors: L
authors: Chen
authors: Qin
authors: Q
authors: Meng
mesh_terms: D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry*; D005260:Female; D005782:Gels; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism; D011237:Predictive Value of Tests; D061251:Primary Cell Culture / Q000379:methods*; D051381:Rats; D013045:Species Specificity
chemical_list: D003470:Culture Media; D005782:Gels; D004364:Pharmaceutical Preparations