{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:55:22Z","timestamp":1790765722460,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,6,27]],"date-time":"2020-06-27T00:00:00Z","timestamp":1593216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:p>Growth and development affect drug\u2010metabolizing 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 [<jats:sup>14<\/jats:sup>C]midazolam microtracer as proof of concept in children. Twelve stable, critically ill children received an oral [<jats:sup>14<\/jats:sup>C]midazolam microtracer (20\u00a0ng\/kg; 60\u00a0Bq\/kg) while receiving intravenous therapeutic midazolam. Blood was sampled up to 24\u00a0hours after dosing. A time\u2010averaged plasma pool per patient was prepared reflecting the mean area under the curve plasma level, and subsequently one pool for each age group (0\u20131\u00a0month, 1\u20136\u00a0months, 0.5\u20132\u00a0years, and 2\u20136\u00a0years). For each pool [<jats:sup>14<\/jats:sup>C]levels were quantified by accelerator mass spectrometry, and metabolites identified by high resolution mass spectrometry. Urine and feces (<jats:italic>n<\/jats:italic>\u00a0=\u00a04) were collected up to 72\u00a0hours. The approach resulted in sufficient sensitivity to quantify individual metabolites in chromatograms. [<jats:sup>14<\/jats:sup>C]1\u2010OH\u2010midazolam\u2010glucuronide was most abundant in all but one age group, followed by unchanged [<jats:sup>14<\/jats:sup>C]midazolam and [<jats:sup>14<\/jats:sup>C]1\u2010OH\u2010midazolam. The small proportion of unspecified metabolites most probably includes [<jats:sup>14<\/jats:sup>C]midazolam\u2010glucuronide and [<jats:sup>14<\/jats:sup>C]4\u2010OH\u2010midazolam. Excretion was mainly in urine; the total recovery in urine and feces was 77\u201394%. This first pediatric pilot study makes clear that using a [<jats:sup>14<\/jats:sup>C]midazolam microtracer is feasible and safe to generate metabolite profiles and study recovery in children. This approach is promising for first\u2010in\u2010child studies to delineate age\u2010related variation in drug metabolite profiles.<\/jats:p>","DOI":"10.1002\/cpt.1884","type":"journal-article","created":{"date-parts":[[2020,5,9]],"date-time":"2020-05-09T20:38:51Z","timestamp":1589056731000},"page":"1003-1009","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Proof of Concept: First Pediatric [<sup>14<\/sup>C]microtracer Study to Create Metabolite Profiles of Midazolam"],"prefix":"10.1111","volume":"108","author":[{"given":"Bianca D.","family":"van Groen","sequence":"first","affiliation":[{"name":"Intensive Care and Department of Pediatric Surgery Erasmus Medical Center \u2013 Sophia Children\u2019s Hospital Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"van Duijn","sequence":"additional","affiliation":[{"name":"TNO Zeist The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan","family":"de Vries","sequence":"additional","affiliation":[{"name":"TNO Zeist The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam G.","family":"Mooij","sequence":"additional","affiliation":[{"name":"Intensive Care and Department of Pediatric Surgery Erasmus Medical Center \u2013 Sophia Children\u2019s Hospital Rotterdam The Netherlands"},{"name":"Department of Pediatrics Leiden University Medical Center Leiden The Netherlands"},{"name":"Department of Pharmacology and Toxicology Radboud University Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"Tibboel","sequence":"additional","affiliation":[{"name":"Intensive Care and Department of Pediatric Surgery Erasmus Medical Center \u2013 Sophia Children\u2019s Hospital Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter H. J.","family":"Vaes","sequence":"additional","affiliation":[{"name":"TNO Zeist The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia N.","family":"de Wildt","sequence":"additional","affiliation":[{"name":"Intensive Care and Department of Pediatric Surgery Erasmus Medical Center \u2013 Sophia Children\u2019s Hospital Rotterdam The Netherlands"},{"name":"Department of Pharmacology and Toxicology Radboud University Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,27]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx800432c"},{"key":"e_1_2_10_2_1","unstructured":"International Conference on Harmonization.Guidance for industry: M3(R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals<https:\/\/www.fda.gov\/media\/71542\/download> (2010). 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