Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group

Abstract

The critical importance of membrane‐bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

“…The neonatal period until infancy is the most interesting in view of the developmental changes that occur in this period. At birth and shortly thereafter major changes are seen in the activity of liver enzymes (75 ) and transporters (76 ). For example, in the second postpartum week undetectable CYP2D6 expression was observed in 13% of liver samples (77 ).…”

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

“…Accordingly, the developmental changes of the OCT1 transporter expression per milligram protein in the liver was not considered in this study because our previous clinical data used as a clinical reference included the age of pediatric patients ranged from 6–15 years 7. Recently, the Pediatric Transporter Working Group reported a lack of knowledge on ontogeny of drug transporters, including the OCT1 transporter 39. As a next step, the ontogeny profile of the OCT1 transporter is being investigated as part of morphine PK simulation studies in neonates and small infants.…”

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

“…Data for human kidney have recently been published; of the solute carrier transporters (SLC), MATE1 and OAT3 were the most abundant (10.8 and 9.7 pmol/mg microsomal protein, respectively), whereas Pgp/MDR1 was the most abundant ATP-binding cassette (ABC) transporter (4.45 pmol/mg microsomal protein) (22). Although data are available concerning renal developmental patterns of transporters in rodent species, minimal expression data are available for human (99). LC-MS/MS methods are currently favoured for measuring transporter abundance in tissue homogenates and subcellular fractions due to the high precision and ability to assess inter-individual and inter-study variability in transporter expression (96).…”

“…Sample availability in particular patient groups will remain a substantial limitation in the generation of these data. In particular, paediatric PBPK models require information on the ontogeny of the abundance and activity of drugmetabolising enzymes and transporters; in contrast to hepatic drug-metabolising enzymes, such data are lacking for human kidney (99,102). Using suitable techniques to quantify differences in protein abundance in different regions of the nephron, such as the convoluted vs. straight portion of proximal tubule, would allow refinement of the current mechanistic models (5).…”