Abstract

The aim of this study was to derive region-specific transporter expression data suitable for In Vitro-to-In Vivo Extrapolation (IVIVE) within a Physiologically-Based Pharmacokinetic (PBPK) Modelling framework. A meta-analysis was performed whereby literary sources reporting region-specific transporter expression obtained via absolute and relative quantification approaches were considered in healthy adult Caucasian individuals. Furthermore, intestinal total membrane protein yield was calculated to enable mechanistic IVIVE via absolute transporter abundances. Where required, authors were contacted for additional information. A refined database was constructed where samples were excluded based on quantification in; non-Caucasian subjects; disease tissue; subjects <18 years old; duplicated samples; non-total membrane matrix; pooled matrices or cDNA. Demographic data was collected where available. The weighted and geometric mean, coefficient of variation and between-study homogeneity was calculated in each of 8 gut segments (duodenum, 2 jejunum, 4 ileum and colon) for 16 transporters. Expression data was normalized to that in the proximal jejunum. From a total of 47 articles, the final database consisted of 2238 measurements for 16 transporters. The solute carrier PepT1 showed the highest jejunal abundance, while MRP2 was the highest abundance ATP-Binding Cassette Transporter. Transporters displaying significant region-specific expression included, IBAT, which showed 18-fold greater terminal ileum expression compared to the proximal jejunum, while MRP3, OCTN1 and OCT1 showed >2-fold higher expression in other regions compared to the proximal jejunum. This is the first systematic analysis incorporating absolute quantification methodology to determine region-specific intestinal transporter expression. It is expected to be beneficial for mechanistic transporter IVIVE in healthy adult Caucasians.