Content and activity of human liver microsomal protein and prediction of individual hepatic clearance in vivo.

Haifeng Zhang,Hongmeng Li,Linjing Jia,Bing Qi,Jun Zhou,Tingting Liu,Binbin Xu,Jie Gao,Hailing Qiao,Qiang Wen,Na Gao,Yan Fang,Xin Tian

doi:10.1038/srep17671

Abstract

The lack of information concerning individual variation in content and activity of human liver microsomal protein is one of the most important obstacles for designing personalized medicines. We demonstrated that the mean value of microsomal protein per gram of liver (MPPGL) was 39.46 mg/g in 128 human livers and up to 19-fold individual variations existed. Meanwhile, the metabolic activities of 10 cytochrome P450 (CYPs) were detected in microsomes and liver tissues, respectively, which showed huge individual variations (200-fold). Compared with microsomes, the activities of liver tissues were much suitable to express the individual variations of CYP activities. Furthermore, individual variations in the in vivo clearance of tolbutamide were successfully predicted with the individual parameter values. In conclusion, we offer the values for MPPGL contents in normal liver tissues and build a new method to assess the in vitro CYP activities. In addition, large individual variations exist in predicted hepatic clearance of tolbutamide. These findings provide important physiological parameters for physiologically-based pharmacokinetics models and thus, establish a solid foundation for future development of personalized medicines.

Highlights

Livers[12,13,14,15,16] and the background information for the samples was often incomplete
The metabolic activities of 10 cytochrome P450 (CYP) were detected in microsomes and liver tissues, respectively, which showed huge individual variations and the variation for some CYPs could reach over 200-fold
The activities of liver tissues were much suitable to express the individual variations of CYP activities

Summary

Introduction

Livers[12,13,14,15,16] and the background information for the samples was often incomplete. The values for MPPGL reported by different groups used different tissue sources, different correction methods to account for losses of microsomal protein and relatively small sample sizes that in turn provided varying mean values[16] These studies did not give significant attention to the potential effects of individual variations in the MPPGL. After the first demonstration of IVIVE in rats in 197718, many subsequent efforts were concentrated on this area In these early studies there was a significantly predictive bias for in vivo clearance from the in vitro metabolic data because existing variation was not considered and instead mean parameter value reconstructed from very small data sets were used[19,20,21,22,23]. Such data will be informative for the design of personalized medicines

Methods

Results

Conclusion