Human Intestinal PEPT1 Transporter Expression and Localization in Preterm and Term Infants

Abstract

The intestinal influx oligopeptide transporter peptide transporter 1 (PEPT1) (SLC15A1) is best known for nutrient-derived di-and tripeptide transport. Its role in drug absorption is increasingly recognized. To better understand the disposition of PEPT1 substrate drugs in young infants, we studied intestinal PEPT1 mRNA expression and tissue localization across the pediatric age range. PEPT1 mRNA expression was determined using real-time reversetranscription polymerase chain reaction in small intestinal tissues collected from surgical procedures (neonates and infants) or biopsies (older children and adolescents). PEPT1 mRNA relative to villin mRNA expression was compared between neonates/infants and older children/adolescents. PEPT1 was visualized in infant tissue using immunohistochemical staining. Other transporters [multidrug resistance protein 1 (MDR1), multidrug resistance-like protein 2 (MRP2), and organic anion transporter polypeptide 2B1 (OATP2B1)] were also stained to describe the localization in relation to PEPT1. Twenty-six intestinal samples (n = 20 neonates/infants, n = 2 pediatric, n = 4 adolescents) were analyzed. The young infant samples were collected at a median (range) gestational age at birth of 29.2 weeks (24.7-40) and postnatal age of 2.4 weeks (0-16.6). The PEPT1 mRNA expression of the neonates/infants was only marginally lower (0.8-fold) than the older children (P < 0.05). Similar and clear apical PEPT1 and MRP2 staining, apical and lateral MDR1 staining, and intraepithelial OATP2B1 staining at the basolateral membrane of the enterocyte were detected in 12 infant and 2 adolescent samples. Although small intestinal PEPT1 expression tended to be lower in neonates than in older children, this difference is small and tissue distribution is similar. This finding suggests similar oral absorption of PEPT1 substrates across the pediatric age range.

Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

“…In contrast to the other intestinal transporters, OATP2B1 gene expression levels were much higher in neonates than in adults . Interestingly, the localization of OATP2B1 remains questionable; 2 studies observed localization of the transporter to the apical membrane of human enterocytes, but another research group, which studied mainly pediatric intestinal tissue samples, detected OATP2B1 in the basolateral membrane . This basolateral localization was also reported by another independent group using 6 healthy human adult jejunal tissue samples .…”

“…Future studies are warranted to elucidate the localization of OATP2B1 and to ascertain if it is subject to developmental changes. Using a total of 26 intestinal tissues samples, which included 19 preterm and term neonates, 1 infant 13.9 weeks old, 2 children, and 4 adolescents, Mooij and colleagues studied the developmental changes in PEPT1 mRNA expression and localization . Although PEPT1 expression appeared to be slightly lower in neonates than in their older counterparts, the tissue distribution was relatively stable among all the samples studied.…”

Oral drug absorption in pediatrics: the intestinal wall, its developmental changes and current tools for predictions

“…The organic anion transporting polypeptide (OATP) 2B1 uptake transporter appears to have a different ontogeny pattern compared with the transporters described earlier. OATP2B1 mRNA expression was found to be 3‐fold higher in neonates compared with adults .…”

“…As for BCRP, data related to the multi-drug associated protein 1 (MRP1) efflux transporter are scarce and only one study reported immunodetectable protein levels comparable to adults from 7 weeks of gestation [123]. Mooij et al [125,133] reported stable mRNA expression of MRP2 from neonates to adults. The expression of influx oligopeptide transporter PEPT1 was investigated in intestinal tissue samples across the pediatric age range [133].…”

“…Mooij et al [125,133] reported stable mRNA expression of MRP2 from neonates to adults. The expression of influx oligopeptide transporter PEPT1 was investigated in intestinal tissue samples across the pediatric age range [133]. PEPT1 mRNA expression of the neonates was only marginally lower (0.8-fold) than the older children.…”