{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T20:04:15Z","timestamp":1772049855453,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002366"],"award-info":[{"award-number":["UL1TR002366"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Naltrexone (NTX), an opioid antagonist metabolized by aldo\u2010keto reductase 1C4 (AKR1C4), is prescribed for psychiatric conditions like eating disorders with variable response. Systemic exposure is highly variable in adults, yet no data exist in children. The purpose of this study was to evaluate NTX exposure in adolescents with eating disorders. Adolescents aged 12\u201321\u2009years with eating disorders underwent postdose blood sampling in the fasted and\/or fed state. NTX and primary active metabolite, 6\u2010\u03b2\u2010naltrexol, were determined by ultra\u2010high performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. DNA was genotyped for <jats:italic>AKR1C4<\/jats:italic> missense mutations associated with decreased activity (rs3829125 and rs17134592). Linear mixed effects modeling was performed. In 21 participants, aged 16.9\u2009\u00b1\u20091.9\u2009years (15\u201321\u2009years), 81% female participants, maximum concentration (C<jats:sub>max<\/jats:sub>) was 90.4\u2009\u00b1\u2009129\u2009nM\/mg\/kg, area under the concentration\u2010time curve from zero to infinity (AUC<jats:sub>0\u2013\u221e<\/jats:sub>) was 166\u2009\u00b1\u2009154\u2009nM\u2009h\/mg\/kg, and varied 63\u2010fold and 21\u2010fold, respectively. Compared with wildtype, those with <jats:italic>AKR1C4<\/jats:italic> allelic variations (<jats:italic>n<\/jats:italic>\u00a0=\u00a07) displayed 3.2\u2010fold higher AUC<jats:sub>0\u2013\u221e<\/jats:sub>, four\u2010fold higher C<jats:sub>max<\/jats:sub> and delayed time to T<jats:sub>max<\/jats:sub>. Linear mixed effects modeling demonstrated a large effect of genotype on AUC<jats:sub>0\u2013\u221e<\/jats:sub> (Cohen's <jats:italic>d<\/jats:italic> \u22122.3) and C<jats:sub>max<\/jats:sub> (Cohen's <jats:italic>d<\/jats:italic> \u22121.4). Food effect was large for AUC<jats:sub>0\u2013\u221e<\/jats:sub> (Cohen's <jats:italic>d<\/jats:italic> 2.6), but highly variable and failed to reach significance for C<jats:sub>max.<\/jats:sub> The respective model accounted for 82% of the variance in NTX AUC<jats:sub>0\u2013\u221e<\/jats:sub> and 46% of the variance in C<jats:sub>max<\/jats:sub>. NTX systemic exposure is highly variable in adolescents with eating disorders and modulated, in part, by <jats:italic>AKR1C4<\/jats:italic> genotype and food intake. These findings may, in part, explain the large degree of interindividual variability observed response to NTX.<\/jats:p>","DOI":"10.1111\/cts.13399","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T06:40:51Z","timestamp":1665038451000},"page":"2732-2743","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Effects of genotype and food on naltrexone exposure in adolescents"],"prefix":"10.1111","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7308-3132","authenticated-orcid":false,"given":"Stephani L.","family":"Stancil","sequence":"first","affiliation":[{"name":"Division of Adolescent Medicine Children's Mercy Hospital \u2013 Kansas City  Kansas City Missouri USA"},{"name":"Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation Children's Mercy Hospital \u2013 Kansas City  Kansas City Missouri USA"},{"name":"Department of Pediatrics University of Missouri\u2010Kansas City School of Medicine  Kansas City Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2760-7481","authenticated-orcid":false,"given":"Michaela","family":"Voss","sequence":"additional","affiliation":[{"name":"Division of Adolescent Medicine Children's Mercy Hospital \u2013 Kansas City  Kansas City Missouri USA"},{"name":"Department of Pediatrics University of Missouri\u2010Kansas City School of Medicine  Kansas City Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0282-0833","authenticated-orcid":false,"given":"Whitney","family":"Nolte","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation Children's Mercy Hospital \u2013 Kansas City  Kansas City Missouri USA"},{"name":"Department of Pediatrics University of Missouri\u2010Kansas City School of Medicine  Kansas City Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0109-0912","authenticated-orcid":false,"given":"John","family":"Tumberger","sequence":"additional","affiliation":[{"name":"Division of Adolescent Medicine Children's Mercy Hospital \u2013 Kansas City  Kansas City Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Adelman","sequence":"additional","affiliation":[{"name":"Department of Student Health and Counseling, Division of Wellness The University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5815-2029","authenticated-orcid":false,"given":"Susan","family":"Abdel\u2010Rahman","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation Children's Mercy Hospital \u2013 Kansas City  Kansas City Missouri USA"},{"name":"Department of Pediatrics University of Missouri\u2010Kansas City School of Medicine  Kansas City Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,10,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.5863\/1551-6776-26.7.675"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/wps.20128"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1089\/cap.2019.0056"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2006.00052.x"},{"key":"e_1_2_9_6_1","first-page":"15","article-title":"Bioequivalence, dose\u2010proportionality, and pharmacokinetics of naltrexone after oral administration","volume":"45","author":"Meyer MC","year":"1984","journal-title":"J Clin Psychiatry"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(02)00368-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2000.tb02107.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1211\/0022357045020"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/03602530802431439"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.039099"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvx041"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116195"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgz261"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2022.898782"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00157.2017"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra035092"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.121.000646"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199912000-00011"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.9.8.677"},{"key":"e_1_2_9_21_1","volume-title":"National Center for Biotechnology Information, National Library of Medicine","author":"Database of Single Nucleotide Polymorphisms (dbSNP)"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-197601030-00002"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2006.07.023"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psc.2018.10.004"},{"key":"e_1_2_9_25_1","first-page":"73","article-title":"The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268)","volume":"26","author":"Coffman BL","year":"1998","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_9_26_1","first-page":"105","article-title":"The metabolism of naltrexone in man","volume":"28","author":"Wall ME","year":"1981","journal-title":"NIDA Res Monogr"},{"key":"e_1_2_9_27_1","first-page":"321","article-title":"Elimination of radioactivity following administration of [15,16\u20103H]naltrexone to rats and Guinea pigs","volume":"6","author":"Ludden TM","year":"1978","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R054114"},{"key":"e_1_2_9_29_1","volume-title":"Diagnostic and statistical manual of mental disorders: DSM\u20105","year":"2013"},{"key":"e_1_2_9_30_1","first-page":"28","article-title":"The clinical global impressions scale: applying a research tool in clinical practice","volume":"4","author":"Busner J","year":"2007","journal-title":"Psychiatry (Edgmont)"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0032639"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eatbeh.2021.101538"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/eat.22180"},{"key":"e_1_2_9_34_1","volume-title":"Bioanalytical Method Validation \u2013 Guidance for Industry","author":"U. S Food and Drug Administration","year":"2018"},{"key":"e_1_2_9_35_1","volume-title":"Assessing the Effects of Food on Drugs in INDs and NDAs \u2013 Clinical Pharmacology Considerations","author":"U.S Food and Drug Administration","year":"2019"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301440"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0811-8"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.27.3.847"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.27.2153"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c120023"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2017.02.016"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13399","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.13399","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13399","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T15:56:16Z","timestamp":1692633376000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,5]]},"references-count":40,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["10.1111\/cts.13399"],"URL":"https:\/\/doi.org\/10.1111\/cts.13399","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,5]]},"assertion":[{"value":"2022-05-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}