A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization
- Department of Bioengineering and Therapeutic Sciences University of California, San Francisco San Francisco California USA, Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation &, Research US Food and Drug Administration Silver Spring Maryland USA, Oak Ridge Institute for Science and Education (ORISE Fellow) Oak Ridge Tennessee USA
- Intensive Care and Department of Pediatric Surgery Erasmus MC‐Sophia Children's Hospital Rotterdam The Netherlands
- Intensive Care and Department of Pediatric Surgery Erasmus MC‐Sophia Children's Hospital Rotterdam The Netherlands, CDTS Consulting BV &, SDD Consulting BV Etten‐Leur The Netherlands
- Department of Pharmacology and Toxicology Radboud University Nijmegen The Netherlands
- Department of Pediatrics Erasmus MC‐Sophia Children's Hospital Rotterdam The Netherlands
- Department of Pathology Erasmus MC Rotterdam The Netherlands
- Department of Pathology Radboudumc Nijmegen The Netherlands
- Office of Research and Standards Office of Generic Drugs Center for Drug Evaluation &, Research US Food and Drug Administration Silver Spring Maryland USA
- Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation &, Research US Food and Drug Administration Silver Spring Maryland USA
- Department of Bioengineering and Therapeutic Sciences University of California, San Francisco San Francisco California USA
- Intensive Care and Department of Pediatric Surgery Erasmus MC‐Sophia Children's Hospital Rotterdam The Netherlands, Department of Pharmacology and Toxicology Radboud University Nijmegen The Netherlands
Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real‐time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p‐glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2‐K and breast cancer resistance protein showed no difference from newborns to adults, despite age‐related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance‐associated protein 2, multidrug resistance‐associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.
- Research Organization:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Organization:
- National Institute of Health (NIH); U.S. Food and Drug Administration (FDA); USDOE; USDOE Office of Science (SC)
- Grant/Contract Number:
- SC0014664
- OSTI ID:
- 1569304
- Journal Information:
- Clinical Pharmacology and Therapeutics, Journal Name: Clinical Pharmacology and Therapeutics Journal Issue: 5 Vol. 106; ISSN 0009-9236
- Publisher:
- Wiley-BlackwellCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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