title: Abundance of Hepatic Transporters in Caucasians: A Meta-Analysis.
abstract: This study aimed to derive quantitative abundance values for key hepatic transporters suitable for in vitro-in vivo extrapolation within a physiologically based pharmacokinetic modeling framework. A meta-analysis was performed whereby data on abundance measurements, sample preparation methods, and donor demography were collated from the literature. To define values for a healthy Caucasian population, a subdatabase was created whereby exclusion criteria were applied to remove samples from non-Caucasian individuals, those with underlying disease, or those with subcellular fractions other than crude membrane. Where a clinically relevant active genotype was known, only samples from individuals with an extensive transporter phenotype 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 nine studies after exclusion criteria were applied. Organic anion transporting polypeptides 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 > multidrug resistance protein 2 > multidrug resistance gene 1. No relationship was found between transporter expression and donor age. To our knowledge, 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 in vitro-in vivo extrapolation, 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.
authors: Simcyp Limited (a Certara Company), Sheffield, United Kingdom.
authors: Howard J
authors: HJ
authors: Burt
authors: Simcyp Limited (a Certara Company), Sheffield, United Kingdom.
authors: Arian Emami
authors: AE
authors: Riedmaier
authors: Simcyp Limited (a Certara Company), Sheffield, United Kingdom.
authors: Matthew D
authors: MD
authors: Harwood
authors: Simcyp Limited (a Certara Company), Sheffield, United Kingdom.
authors: H Kim
authors: HK
authors: Crewe
authors: Simcyp Limited (a Certara Company), Sheffield, United Kingdom.
authors: Katherine L
authors: KL
authors: Gill
authors: Simcyp Limited (a Certara Company), Sheffield, United Kingdom sibylle.neuhoff@certara.com.
authors: Sibylle
authors: S
authors: Neuhoff
mesh_terms: D006801:Humans; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3 / Q000378:metabolism*; D044465:White People
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3