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Article ; Online: Maximum likelihood estimation of renal transporter ontogeny profiles for pediatric PBPK modeling.

Hunt, J Porter / Dubinsky, Samuel / McKnite, Autumn M / Cheung, Kit Wun Kathy / van Groen, Bianca D / Giacomini, Kathleen M / de Wildt, Saskia N / Edginton, Andrea N / Watt, Kevin M

CPT: pharmacometrics & systems pharmacology

2024 Volume 13, Issue 4, Page(s) 576–588

Abstract: Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically-based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ... ...

Abstract	Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically-based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ontogeny profiles for RT activity in children, especially neonates, to predict drug disposition. Therefore, RT expression measurements from human kidney postmortem cortical tissue samples were normalized to represent a fraction of mature RT activity. Using these data, maximum likelihood estimated the distributions of RT activity across the pediatric age spectrum, including preterm and term neonates. PBPK models of four RT substrates (acyclovir, ciprofloxacin, furosemide, and meropenem) were evaluated with and without ontogeny profiles using average fold error (AFE), absolute average fold error (AAFE), and proportion of observations within the 5-95% prediction interval. Novel maximum likelihood profiles estimated ontogeny distributions for the following RT: OAT1, OAT3, OCT2, P-gp, URAT1, BCRP, MATE1, MRP2, MRP4, and MATE-2 K. Profiles for OAT3, P-gp, and MATE1 improved infant furosemide and neonate meropenem PBPK model AFE from 0.08 to 0.70 and 0.53 to 1.34 and model AAFE from 12.08 to 1.44 and 2.09 to 1.36, respectively, and improved the percent of data within the 5-95% prediction interval from 48% to 98% for neonatal ciprofloxacin simulations, respectively. Even after accounting for other critical population-specific maturational differences, novel RT ontogeny profiles substantially improved neonatal PBPK model performance, providing validated estimates of maturational differences in RT activity for optimal dosing in children.
MeSH term(s)	Infant ; Infant, Newborn ; Child ; Humans ; Likelihood Functions ; Meropenem ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Furosemide ; Neoplasm Proteins ; Models, Biological ; Ciprofloxacin
Chemical Substances	Meropenem (FV9J3JU8B1) ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Furosemide (7LXU5N7ZO5) ; Neoplasm Proteins ; Ciprofloxacin (5E8K9I0O4U)
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13102
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Article ; Online: Innovative approaches and recent advances in the study of ontogeny of drug metabolism and transport.

van Groen, Bianca D / Allegaert, Karel / Tibboel, Dick / de Wildt, Saskia N

British journal of clinical pharmacology

2020 Volume 88, Issue 10, Page(s) 4285–4296

Abstract: The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric ... ...

Abstract	The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric continuum. However, knowledge gaps exist on these changes and their clinical impact. Filling these gaps may aid better prediction of drug disposition and creation of age-appropriate dosing guidelines. We present innovative approaches to study these developmental changes in relation to drug metabolism and transport. First, analytical methods such as including liquid chromatography-mass spectrometry for proteomic analyses allow quantitation of the expressions of a wide variety of proteins, e.g. membrane transporters, in a small piece of organ tissue. The latter is specifically important for paediatric research, where tissues are scarcely available. Second, innovative study designs using radioactive labelled microtracers allowed study-without risk for the child-of the oral bioavailability of compounds used as markers for certain drug metabolism pathways. Third, the use of modelling and simulation to support dosing recommendations for children is supported by both the European Medicines Agency and the US Food and Drug Administration. This may even do away with the need for a paediatric trial. Physiologically based pharmacokinetics models, which include age-specific physiological information are, therefore, increasingly being used, not only to aid paediatric drug development but also to improve existing drug therapies.
MeSH term(s)	Biological Availability ; Child ; Computer Simulation ; Humans ; Metabolic Clearance Rate ; Pharmaceutical Preparations ; Proteomics
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2020-09-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.14534
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Article ; Online: Alternative Splicing of the SLCO1B1 Gene: An Exploratory Analysis of Isoform Diversity in Pediatric Liver.

van Groen, Bianca D / Bi, Chengpeng / Gaedigk, Roger / Staggs, Vincent S / Tibboel, Dick / de Wildt, Saskia N / Leeder, J Steven

Clinical and translational science

2020 Volume 13, Issue 3, Page(s) 509–519

Abstract: The hepatic influx transporter OATP1B1 (SLCO1B1) plays an important role in the disposition of endogenous substrates and drugs prescribed to children. Alternative splicing increases the diversity of protein products from > 90% of human genes and may be ... ...

Abstract	The hepatic influx transporter OATP1B1 (SLCO1B1) plays an important role in the disposition of endogenous substrates and drugs prescribed to children. Alternative splicing increases the diversity of protein products from > 90% of human genes and may be triggered by developmental signals. As concentrations of several endogenous OATP1B1 substrates change during growth and development, with this exploratory study we investigated age-dependent alternative splicing of SLCO1B1 mRNA in 97 postmortem livers (fetus-adolescents). Twenty-seven splice variants were detected; 10 were confirmed by additional bioinformatic analyses and verified by quantitative polymerase chain reaction, and selected for detailed analysis based on relative abundance, association with age, and overlap with an adjacent gene. Two splice variants code for reference OATP1B1 protein, and eight code for truncated proteins. The expression of eight isoforms was associated with age. We conclude that alternative splicing of SLCO1B1 occurs frequently in children; although the functional consequences remain unknown, the data raise the possibility of a regulatory role for alternative splicing in mediating developmental changes in drug disposition.
MeSH term(s)	Aborted Fetus ; Adolescent ; Age Factors ; Alternative Splicing ; Child ; Child, Preschool ; Gene Expression Regulation, Developmental ; Humans ; Infant ; Infant, Newborn ; Liver/metabolism ; Liver-Specific Organic Anion Transporter 1/genetics ; Liver-Specific Organic Anion Transporter 1/metabolism ; Netherlands ; Organic Anion Transporters/genetics ; Organic Anion Transporters/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; RNA-Seq ; Solute Carrier Proteins/genetics ; Solute Carrier Proteins/metabolism ; Stillbirth
Chemical Substances	Liver-Specific Organic Anion Transporter 1 ; Organic Anion Transporters ; Protein Isoforms ; SLCO1B1 protein, human ; SLCO1B7 protein, human ; Solute Carrier Proteins
Language	English
Publishing date	2020-01-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.12733
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Article ; Online: Prospective Investigation of the Performance of 2 Gamma-Hydroxybutyric Acid Tests: DrugCheck GHB Single Test and Viva-E GHB Immunoassay.

Smits, Thomas A / Gresnigt, Femke M J / van Groen, Bianca D / Franssen, Eric J F / Attema-de Jonge, Milly E

Therapeutic drug monitoring

2019 Volume 42, Issue 1, Page(s) 139–145

Abstract: Background: Gamma-hydroxybutyric acid (GHB) is a recreational drug with central nervous system depressing effects that is often abused. A urine GHB point-of-care test can be of great diagnostic value. The objective of this prospective study was to ... ...

Abstract	Background: Gamma-hydroxybutyric acid (GHB) is a recreational drug with central nervous system depressing effects that is often abused. A urine GHB point-of-care test can be of great diagnostic value. The objective of this prospective study was to determine the performance of the new DrugCheck GHB Single Test and the Viva-E GHB immunoassay for urine samples in emergency department patients. Methods: Patients presented to the emergency department of the OLVG hospital in Amsterdam with a Glasgow Coma Scale score <15 and potential drug of abuse intoxication were included in the study. Between June 2016 and October 2017, 375 patients were included. Using the DrugCheck GHB Single Test (Express Diagnostics Int'l, Blue Earth, MN) and the Viva-E GHB immunoassay (Siemens Healthineers, The Hague, the Netherlands), patients' urine samples were tested for GHB (cutoff for a positive result, 10 or 50 mcg/mL GHB). To ensure quality, the results obtained were compared with those generated using a validated gas chromatography method. The tests were considered reliable if specificity and sensitivity were both >90%. Possible cross-reactivity with ethanol was investigated by analyzing ethanol concentrations in patients' samples. Results: Seventy percentage of the included patients was men, and the median age was 34 years old. The DrugCheck GHB Single Test's specificity and sensitivity were 90.0% and 72.9%, respectively, and using 50 mcg/mL as a cutoff value, its specificity and sensitivity improved to 96.7% and 75.0%, respectively. Serum and urine ethanol levels in the false-positive group were significantly higher compared with those in the true-negative group. The specificity and sensitivity of the Viva-E GHB immunoassay (cutoff value of 50 mcg/mL and excluding samples with ethanol levels ≥2.0 g/L) were 99.4% and 93.5%, respectively. Conclusions: The DrugCheck GHB Single Test's specificity was sufficient, whereas its sensitivity was poor, making it unsuitable for use at point-of-care. Contrarily, using 50 mcg/mL as the cutoff value and excluding samples with ethanol levels ≥2.0 g/L, the Viva-E GHB immunoassay showed acceptable results to detect clinically relevant GHB intoxications.
MeSH term(s)	Adult ; Ascorbic Acid/chemistry ; Ascorbic Acid/urine ; Chromatography, Gas ; Ethanol/chemistry ; Ethanol/urine ; False Positive Reactions ; Female ; Humans ; Hydroxybutyrates/chemistry ; Hydroxybutyrates/urine ; Immunoassay/methods ; Male ; Sensitivity and Specificity
Chemical Substances	Hydroxybutyrates ; 4-hydroxybutyric acid (30IW36W5B2) ; Ethanol (3K9958V90M) ; Ascorbic Acid (PQ6CK8PD0R)
Language	English
Publishing date	2019-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	424443-6
ISSN	1536-3694 ; 0163-4356
ISSN (online)	1536-3694
ISSN	0163-4356
DOI	10.1097/FTD.0000000000000677
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Article ; Online: Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters.

Cheung, Kit Wun Kathy / van Groen, Bianca D / Burckart, Gilbert J / Zhang, Lei / de Wildt, Saskia N / Huang, Shiew-Mei

Journal of clinical pharmacology

2019 Volume 59 Suppl 1, Page(s) S56–S69

Abstract: Developmental changes in the biological processes involved in the disposition of drugs, such as membrane transporter expression and activity, may alter the drug exposure and clearance in pediatric patients. Physiologically based pharmacokinetic (PBPK) ... ...

Abstract	Developmental changes in the biological processes involved in the disposition of drugs, such as membrane transporter expression and activity, may alter the drug exposure and clearance in pediatric patients. Physiologically based pharmacokinetic (PBPK) models take these age-dependent changes into account and may be used to predict drug exposure in children. As a result, this mechanistic-based tool has increasingly been applied to improve pediatric drug development. Under the Prescription Drug User Fee Act VI, the US Food and Drug Administration has committed to facilitate the advancement of PBPK modeling in the drug application review process. Yet, significant knowledge gaps on developmental biology still exist, which must be addressed to increase the confidence of prediction. Recently, more data on ontogeny of transporters have emerged and supplied a missing piece of the puzzle. This article highlights the recent findings on the ontogeny of transporters specifically in the intestine, liver, and kidney. It also provides a case study that illustrates the utility of incorporating this information in predicting drug exposure in children using a PBPK approach. Collaborative work has greatly improved the understanding of the interplay between developmental physiology and drug disposition. Such efforts will continue to be needed to address the remaining knowledge gaps to enhance the application of PBPK modeling in drug development for children.
MeSH term(s)	Child ; Child, Preschool ; Drug Development ; Humans ; Infant ; Infant, Newborn ; Kidney/metabolism ; Liver/metabolism ; Membrane Transport Proteins/metabolism ; Models, Biological ; Pharmaceutical Preparations/metabolism
Chemical Substances	Membrane Transport Proteins ; Pharmaceutical Preparations
Language	English
Publishing date	2019-09-22
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1489
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Article: A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept.

Hartman, Stan J F / Swaving, Joost G E / van Beek, Stijn W / van Groen, Bianca D / de Hoop, Marika / van der Zanden, Tjitske M / Ter Heine, Rob / de Wildt, Saskia N

Frontiers in pharmacology

2020 Volume 11, Page(s) 592204

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2020-12-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2020.592204
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Article ; Online: Proof of Concept: First Pediatric [

van Groen, Bianca D / van Duijn, Esther / de Vries, Arjan / Mooij, Miriam G / Tibboel, Dick / Vaes, Wouter H J / de Wildt, Saskia N

Clinical pharmacology and therapeutics

2020 Volume 108, Issue 5, Page(s) 1003–1009

Abstract: Growth and development affect drug-metabolizing enzyme activity thus could alter the metabolic profile of a drug. Traditional studies to create metabolite profiles and study the routes of excretion are unethical in children due to the high radioactive ... ...

Abstract	Growth and development affect drug-metabolizing enzyme activity thus could alter the metabolic profile of a drug. Traditional studies to create metabolite profiles and study the routes of excretion are unethical in children due to the high radioactive burden. To overcome this challenge, we aimed to show the feasibility of an absorption, distribution, metabolism, and excretion (ADME) study using a [
MeSH term(s)	Administration, Intravenous ; Administration, Oral ; Age Factors ; Biotransformation ; Carbon Radioisotopes/administration & dosage ; Carbon Radioisotopes/blood ; Carbon Radioisotopes/pharmacokinetics ; Carbon Radioisotopes/urine ; Child ; Child, Preschool ; Critical Illness ; Feasibility Studies ; Feces/chemistry ; Female ; Humans ; Hypnotics and Sedatives/administration & dosage ; Hypnotics and Sedatives/blood ; Hypnotics and Sedatives/pharmacokinetics ; Hypnotics and Sedatives/urine ; Infant ; Infant, Newborn ; Intensive Care Units, Pediatric ; Intestinal Elimination ; Male ; Mass Spectrometry ; Midazolam/administration & dosage ; Midazolam/blood ; Midazolam/pharmacokinetics ; Midazolam/urine ; Proof of Concept Study ; Renal Elimination
Chemical Substances	Carbon Radioisotopes ; Hypnotics and Sedatives ; Midazolam (R60L0SM5BC)
Language	English
Publishing date	2020-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.1884
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Article ; Online: Pediatric Pharmacokinetics and Dose Predictions: A Report of a Satellite Meeting to the 10th Juvenile Toxicity Symposium.

van Groen, Bianca D / Pilla Reddy, Venkatesh / Badée, Justine / Olivares-Morales, Andrés / Johnson, Trevor N / Nicolaï, Johan / Annaert, Pieter / Smits, Anne / de Wildt, Saskia N / Knibbe, Catherijne A J / de Zwart, Loeckie

Clinical and translational science

2020 Volume 14, Issue 1, Page(s) 29–35

Abstract: On April 24, 2019, a symposium on Pediatric Pharmacokinetics and Dose Predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. This symposium brought together scientists from academia, industry, and clinical research ... ...

Abstract	On April 24, 2019, a symposium on Pediatric Pharmacokinetics and Dose Predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. This symposium brought together scientists from academia, industry, and clinical research organizations with the aim to update each other on the current knowledge on pediatric drug development. Through more knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically-based pharmacokinetic (PBPK) models, we have gained a more integrated understanding of age-related differences in pharmacokinetics (PKs), Relevant examples were presented during the meeting. PBPK may be considered the gold standard for pediatric PK prediction, but still it is important to know that simpler methods, such as allometry, allometry combined with maturation function, functions based on the elimination pathway, or linear models, also perform well, depending on the age range or the mechanisms involved. Knowledge from different methods and information sources should be combined (e.g., microdosing can reveal early read-out of age-related differences in exposure), and such results can be a value to verify models. To further establish best practices for dose setting in pediatrics, more in vitro and in vivo research is needed on aspects such as age-related changes in the exposure-response relationship and the impact of disease on PK. New information coupled with the refining of model-based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials.
MeSH term(s)	Age Factors ; Child ; Child Development/physiology ; Clinical Trials as Topic ; Congresses as Topic ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Developmental ; Glucuronosyltransferase/genetics ; Glucuronosyltransferase/metabolism ; Humans ; Metabolic Clearance Rate/physiology ; Models, Biological ; Research Design ; Tissue Distribution
Chemical Substances	Cytochrome P-450 Enzyme System (9035-51-2) ; Glucuronosyltransferase (EC 2.4.1.17)
Language	English
Publishing date	2020-08-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.12843
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Article ; Online: The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study.

van Groen, Bianca D / Krekels, Elke H J / Mooij, Miriam G / van Duijn, Esther / Vaes, Wouter H J / Windhorst, Albert D / van Rosmalen, Joost / Hartman, Stan J F / Hendrikse, N Harry / Koch, Birgit C P / Allegaert, Karel / Tibboel, Dick / Knibbe, Catherijne A J / de Wildt, Saskia N

Clinical pharmacology and therapeutics

2020 Volume 109, Issue 1, Page(s) 140–149

Abstract: Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates ...

Abstract	Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1-OH-midazolam (OHM) and 1-OH-midazolam-glucuronide (OHMG) after oral administration are largely unknown for the entire pediatric age span. We aimed to fill these knowledge gaps with a pediatric [
MeSH term(s)	Administration, Oral ; Biological Availability ; Child ; Child, Preschool ; Critical Illness ; Cytochrome P-450 CYP3A/metabolism ; Female ; Glucuronides/metabolism ; Humans ; Hypnotics and Sedatives/pharmacokinetics ; Infant ; Intestines/physiology ; Liver/metabolism ; Male ; Metabolic Clearance Rate ; Midazolam/pharmacokinetics
Chemical Substances	Glucuronides ; Hypnotics and Sedatives ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Midazolam (R60L0SM5BC)
Language	English
Publishing date	2020-06-28
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.1890
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Article ; Online: A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization.

Cheung, Kit Wun Kathy / van Groen, Bianca D / Spaans, Edwin / van Borselen, Marjolein D / de Bruijn, Adrianus C J M / Simons-Oosterhuis, Ytje / Tibboel, Dick / Samsom, Janneke N / Verdijk, Robert M / Smeets, Bart / Zhang, Lei / Huang, Shiew-Mei / Giacomini, Kathleen M / de Wildt, Saskia N

Clinical pharmacology and therapeutics

2019 Volume 106, Issue 5, Page(s) 1083–1092

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Adolescent ; Adult ; Age Factors ; Aged ; Child ; Child, Preschool ; Chromatography, Liquid ; Female ; Humans ; Infant ; Infant, Newborn ; Kidney Cortex/metabolism ; Male ; Membrane Transport Proteins/metabolism ; Middle Aged ; Pregnane X Receptor/metabolism ; Proteomics/methods ; RNA, Messenger/biosynthesis ; Real-Time Polymerase Chain Reaction ; Tandem Mass Spectrometry ; Young Adult
Chemical Substances	Membrane Transport Proteins ; Pregnane X Receptor ; RNA, Messenger
Language	English
Publishing date	2019-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.1516
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