Ontogeny of human hepatic and intestinal transporter gene expression during childhood: age matters.
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 2(-∆∆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.
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Miriam G
MG
Mooij
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Ute I
UI
Schwarz
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Barbara A E
BA
de Koning
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
J Steven
JS
Leeder
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Roger
R
Gaedigk
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Janneke N
JN
Samsom
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Edwin
E
Spaans
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Johannes B
JB
van Goudoever
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Dick
D
Tibboel
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.).
Richard B
RB
Kim
Intensive Care and Department of Pediatric Surgery (M.G.M., S.N.W., B.A.E.K., E.S., D.T.), and Laboratory of Pediatrics, Division of Gastroenterology and Nutrition (J.N.S.), Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada (U.I.S., R.B.K.); Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (J.S.L., R.G.); Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, and Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands (J.B.G.) s.dewildt@erasmusmc.nl.
Saskia N
SN
de Wildt
D000293:Adolescent; D000328:Adult; D001692:Biological Transport / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D063990:Gene Ontology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human