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.

Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens

“…Low levels of MATE1, OCT3, and P-gp were also reported, which verify the observations of the present study. Our findings are also supported by a recent meta-analysis of Burt et al 40 reporting OATP1B3, OATP1B1, OCT1, and OATP2B1 as the most abundant liver transporters and MATE1, P-gp, and MRP2 as the lowest.…”

“…It should be noted that all mentioned studies measured BCRP protein abundance in isolated or enriched membrane fractions, which led to the enrichment of the studied protein in measured samples compared with the whole‐tissue lysate analyzed in the present study . Similarly, the meta‐analysis of Burt et al . reported very low BCRP levels, which constituted only 0.34% of 11 transporter proteins in the liver (only the study by Wang et al .…”

“…Although protein levels can vary in different study populations, it is expected that the described differences most likely result from different sample preparation (the studies evaluated membrane fraction vs. whole‐tissue lysate in the present study) and different analytical procedures (e.g., global proteomics approach). In addition, high intersubject variance, the highest reported for OATP1B3, OATP1B1, MRP2, and MRP1, could contribute to the observed discrepancies …”

“…It should be noted that all mentioned studies measured BCRP protein abundance in isolated or enriched membrane fractions, which led to the enrichment of the studied protein in measured samples compared with the whole-tissue lysate analyzed in the present study. 23 Similarly, the meta-analysis of Burt et al 40 reported very low BCRP levels, which constituted only 0.34% of 11 transporter proteins in the liver (only the study by Wang et al 39 met entry criteria). Because the ABCG2 polymorphisms were shown to be associated with ABCG2 expression levels, 41 this meta-analysis, similar to our study, included exclusively wild-type subjects (all donors from the present study were genotyped for ABCG2 c.421C > A, rs2231142, polymorphism, and were defined as wild-type carriers; results not shown).…”

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

“…The published relative scalar of 5.1, which was established using a relative scaling method, was in this study corrected for the absolute abundance of OCT1 (1.63 pmol OCT1/millions of hepatocytes from the Simcyp database), hence, an overall scalar of 3.13 was used for all simulations.…”