Ontogeny of Human Hepatic and Intestinal Transporter Gene Expression during Childhood: Age Matters

Abstract

Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression. Our study assessed agerelated gene expression of hepatic and intestinal drug transporters. Multidrug resistance protein 2 (MRP2), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3 expression was determined in postmortem liver samples (fetal n = 6, neonatal n = 19, infant n = 7, child n = 2, adult n = 11) and multidrug resistance 1 (MDR1) expression in 61 pediatric liver samples. Intestinal expression of MDR1, MRP2, and OATP2B1 was determined in surgical small bowel samples (neonates n = 15, infants n = 3, adults n = 14). Using real-time reverse-transcription polymerase chain reaction, we measured fetal and pediatric gene expression relative to 18S rRNA (liver) and villin (intestines), and we compared it with adults using the 2 2ΔΔCt method. Hepatic expression of MRP2, OATP1B1, and OATP1B3 in all pediatric age groups was significantly lower than in adults. Hepatic MDR1 mRNA expression in fetuses, neonates, and infants was significantly lower than in adults. Neonatal intestinal expressions of MDR1 and MRP2 were comparable to those in adults. Intestinal OATP2B1 expression in neonates was significantly higher than in adults. We provide new data that show organ-and transporter-dependent differences in hepatic and intestinal drug transporter expression in an age-dependent fashion. This suggests that substrate drug absorption mediated by these transporters may be subject to age-related variation in a transporter dependent pattern.

Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver

“…Thus, our results are not inconsistent with the results reported by Prasad et al (2014). Mooij et al (2014) investigated OATP1B1 and OATP1B3 mRNA expression in 45 liver specimens from fetal to adult age. Compared with the adult liver, OATP1B1 mRNA expression was 20-fold lower than that in fetal liver samples, 500-fold lower than that in neonates, and 90-fold lower than that in infants.…”

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

“…Stable mRNA expression of small intestinal MDR1 from neonatal age onward was also found in other studies (Fakhoury et al, 2005;Miki et al, 2005;Mizuno et al, 2014;Mooij et al, 2014). In a previous study, MRP2 mRNA expression in the small intestines was also stable during infant age, but OATP2B1 expression in neonates was about three times higher than in adults (Mooij et al, 2014).…”

“…In a previous study, MRP2 mRNA expression in the small intestines was also stable during infant age, but OATP2B1 expression in neonates was about three times higher than in adults (Mooij et al, 2014). This suggests that intestinal membrane transporters show stable or higher expression during childhood and that a developmental expression might occur before birth.…”

“…Isolation and cDNA synthesis have been previously described (Mooij et al, 2014). In brief, frozen tissue samples were mechanically homogenized on ice.…”

Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation

“…In pediatrics, these models account for the ontogeny of different enzymes, changing tissue volumes and composition, as well as blood flows to these organs (6). At this time, research into the ontogeny of transporters (7,8) lags behind that of hepatic enzymes.…”