The Regional-Specific Relative and Absolute Expression of Gut Transporters in Adult Caucasians: A Meta-Analysis

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) modeling 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 were collected where available. The weighted and geometric mean, coefficient of variation, and between-study homogeneity was calculated in each of eight gut segments (duodenum, two jejunum, four ileum, and colon) for 16 transporters. Expression data were 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 peptide transporter 1 (PepT1) showed the highest jejunal abundance, while multidrug resistance-associated protein (MRP) 2 was the highest abundance ATP-binding cassette transporter. Transporters displaying significant region-specific expression included the ileal bile acid transporter, which showed 18-fold greater terminal ileum expression compared with the proximal jejunum, while MRP3, organic cation transporter type 1 (OCTN1), and OCT1 showed >2-fold higher expression in other regions compared with 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. SIGNIFICANCE STATEMENT Given the burgeoning reports of absolute transporter abundances in the human intestine, the incorporation of such information into mechanistic IVIVE-PBPK models could offer a distinct advantage in facilitating the robust assessment of the impact of gut transporters on drug disposition. The systematic and formal assessment via a literature meta-analysis described herein, enables assignment of the regional-specific expression, absolute transporter abundances, interindividual variability, and other associated scaling factors to healthy Caucasian populations within PBPK models. The resulting values are available to incorporate into PBPK models, and offer a verifiable account describing intestinal transporter expression within PBPK models for persons wishing to utilize them. Furthermore, these data facilitate the development of appropriate IVIVE scaling strategies using absolute transporter abundances.

In Vivo Gene Expression Profile of Human Intestinal Epithelial Cells: From the Viewpoint of Drug Metabolism and Pharmacokinetics

“…5A, left). Consistent with our data, Harwood et al showed that gene expression levels of PEPT1 in the human ileum were higher than those of other transporters (Harwood et al, 2019). As for the basolateral transporters, the proportions in the ileum were 41% (OSTβ), 30% (OSTα), 10% (MRP3), 9% (MRP1), and 7% (MRP5) (Fig.…”

Quantitative Proteomics of Clinically Relevant Drug-Metabolizing Enzymes and Drug Transporters and Their Intercorrelations in the Human Small Intestine

“…In previous targeted proteomic studies, quantifying OATP1A2 above limits of quantification was challenging in intestinal samples Drozdzik et al, 2014;Nakamura et al, 2016). A recent meta-analysis assessing relative and absolute regional expression of transporters in the intestine highlighted the challenges for assigning OATP1A2 expression directly into PBPK models in which a mechanistic intestinal model is described (Harwood et al, 2019). In this study, however, the abundance of OATP1A2 in all 16 samples was found to be above the limit of quantification at relatively similar levels to OST-a and OST-b.…”

“…Therefore, to make meaningful progress toward achieving accurate PBPK predictions of absorption and gut wall clearance of orally administered drugs from the small intestine, it is vital that the abundance of DMEs and drug transporters and their variations are quantified in the small intestine. To capture the variability in a population, quantification of these protein abundances should be achieved in a sufficient number of individuals across different patient populations (Drozdzik et al, 2018;Harwood et al, 2019). The invasive nature of procedures and limited access to dedicated intestinal tissue banks has so far precluded such a large-scale study.…”

“…The invasive nature of procedures and limited access to dedicated intestinal tissue banks has so far precluded such a large-scale study. Despite this challenge, published data do exist for DMEs and transporters in a relatively small number of samples Sato et al, 2014;Akazawa et al, 2018;Harwood et al, 2019). Regional variations in the abundance of some DMEs and drug transporters have also been reported in relatively few studies, whereas no variations were observed in other studies (Drozdzik et al, 2014(Drozdzik et al, , 2018.…”

Examination of Physiologically‐Based Pharmacokinetic Models of Rosuvastatin

“…M-III focused on capturing rosuvastatin's delayed absorption, and the authors explained that while the distribution of BCRP (higher in the duodenum and jejunum) could cause the delay, a clinical genotyping study of subjects with reduced BCRP activity did not shift the t max as would have been expected 33 . The authors then postulated that basolateral transport by OST /ß 28 may explain the α absorption delay if OST /ß is highly expressed in the middle to terminal sections of the ileum α (however a recent meta-analysis found the regional expression for OST /ß to be more uniform 34 ). Mα III input a gut apical uptake CL int,T which was "model fit".…”