The aim of this study was to derive quantitative abundance values for key hepatic transporters suitable for in vitro-in vivo extrapolation (IVIVE) within a physiologically-based pharmacokinetic modeling framework. A meta-analysis was performed whereby abundance measurements, sample preparation method and donor demography were collated from literature. In order to define values for a healthy Caucasian population, a sub-database was created whereby exclusion criteria were applied to remove samples from non-Caucasian individuals, those with underlying disease or subcellular fractions other than crude membrane. Where a clinically relevant active genotype was known, only samples for the wild type were included. Authors were contacted directly when additional information was required. After removing duplicated samples, the weighted mean, geometric mean, standard deviation, coefficient of variation and between-study homogeneity of transporter abundances were determined. From the complete database containing 24 transporters, suitable abundance data were available for 11 hepatic transporters from 9 studies after exclusion criteria were applied. OATP1B1 and OATP1B3 showed the highest population abundance in healthy adult Caucasians. For several transporters the variability in abundance was reduced significantly once the exclusion criteria were applied. The highest variability was observed for OATP1B3>OATP1B1>MRP2>MDR1. No relationship was found between transporter expression and donor age. This study provides the first in-depth analysis of current quantitative abundance data for a wide range of hepatic transporters, with the aim of using these data for IVIVE and highlights the significance of investigating the background of tissue(s) used in quantitative transporter proteomic studies. Similar studies are now warranted for other ethnicities.
十月 1, 2016
Author(s): Howard Burt, Arian Emami Riedmaier, Matthew Harwood, Kim Crewe, Katherine Gill, Sibylle Neuhoff
Year: 十月 1, 2016