Ontogeny of human hepatic and intestinal transporter gene expression during childhood: Age matters

Authors

Miriam G. Mooij, Erasmus MC Sophia Children's Hospital
Ute I. Schwarz, Erasmus MC Sophia Children's Hospital
Barbara A.E. De Koning, Erasmus MC Sophia Children's Hospital
J. Steven Leeder, Children's Mercy Hospitals and Clinics
Roger Gaedigk, Children's Mercy Hospitals and Clinics
Janneke N. Samsom, Erasmus MC Sophia Children's Hospital
Edwin Spaans, Erasmus MC Sophia Children's Hospital
Johannes B. Van Goudoever, Emma Kinderziekenhuis

Document Type

Article

Publication Date

1-1-2014

Journal

Drug Metabolism and Disposition

Volume

42

Issue

8

First Page

1268

Last Page

1274

URL with Digital Object Identifier

10.1124/dmd.114.056929

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 age-related 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 22 -Delta;Delta;Ct 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. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.