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The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood\u2010flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP\u2010glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood\u2010flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age\u2010dependent factors into the pediatric system platform resulted in reasonable prediction for an age\u2010dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age\u2010dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression\/activity and hepatic blood\u2010flow.<\/jats:p>","DOI":"10.1002\/psp4.12306","type":"journal-article","created":{"date-parts":[[2018,6,19]],"date-time":"2018-06-19T16:56:38Z","timestamp":1529427398000},"page":"464-473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants"],"prefix":"10.1002","volume":"7","author":[{"given":"Chie","family":"Emoto","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"},{"name":"Department of Pediatrics, College of Medicine University of Cincinnati Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor N.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Certara UK Limited, Simcyp Division Sheffield S1 2BJ United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Neuhoff","sequence":"additional","affiliation":[{"name":"Certara UK Limited, Simcyp Division Sheffield S1 2BJ United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hahn","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Vinks","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"},{"name":"Department of Pediatrics, College of Medicine University of Cincinnati Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"},{"name":"Department of Pediatrics, College of Medicine University of Cincinnati Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,6,19]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00292926"},{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","unstructured":"Nelson K.L. 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