{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T08:03:25Z","timestamp":1771315405690,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:p>\n                    Methadone is a utilitarian opioid with growing use for anesthesia and postoperative pain. Methadone pharmacokinetic models have evolved over time; however, there is no comprehensive population pharmacokinetic model. This investigation developed a population model for\n                    <jats:italic>R<\/jats:italic>\n                    (\u2212)\u2010 and\n                    <jats:italic>S<\/jats:italic>\n                    (+)\u2010enantiomers of methadone and the primary metabolite 2\u2010ethyl\u20101,5\u2010dimethyl\u20103,3\u2010diphenylpyrrolidine (EDDP) in plasma and urine, incorporating enantiomeric disposition, metabolism, genetics, renal elimination, and frequent and long\u2010duration sampling, to adequately describe both distribution and elimination. In this secondary analysis of previously obtained data from 64 adults sampled for 96\u2009hours, a compartmental model utilizing eight distinct measurement categories of drug and metabolite concentration that unified enantiomer kinetics was developed using nonlinear mixed effects techniques. Potential model covariates for weight, race, sex,\n                    <jats:italic>CYP2B6<\/jats:italic>\n                    genetics, and\n                    <jats:italic>CYP2C19<\/jats:italic>\n                    genetics were tested. The final unified three\u2010compartment population model accounted for significant and systematic enantiomer\u2010specific differences in volumes of distribution, intercompartmental and elimination clearances between\n                    <jats:italic>R<\/jats:italic>\n                    (\u2212)\u2010 and\n                    <jats:italic>S<\/jats:italic>\n                    (+)\u2010methadone, by estimating\n                    <jats:italic>S<\/jats:italic>\n                    (+)\/\n                    <jats:italic>R<\/jats:italic>\n                    (\u2212) ratios. The model incorporated weight and CYP2B6 genotype but not CYP2C19 genotype, sex or race as covariates. Intersubject variability was consistent with that of other intravenous opioids.\n                    <jats:italic>S<\/jats:italic>\n                    (+)\/\n                    <jats:italic>R<\/jats:italic>\n                    (\u2212) ratios were consistent with known enantiomeric differences in \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    \u2010acid glycoprotein binding and in\u00a0vitro biotransformation, and disposition was explainable by enantiomeric restrictive plasma protein binding effects on drug distribution, pharmacokinetic flow, and intrinsic hepatic clearance (CYP2B6\u2010catalyzed metabolism). The population model may be applicable to pharmacokinetically guided intravenous methadone dosing and CYP2B6\u2010mediated drug interactions in perioperative and critical care settings.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70147","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T09:23:19Z","timestamp":1764580999000},"page":"739-750","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population Pharmacokinetics of Intravenous Methadone Enantiomers in Adults: A\u00a0Comprehensive Model"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8993-3936","authenticated-orcid":false,"given":"Thomas K.","family":"Henthorn","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy Practice and Pharmaceutical Sciences Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6613-922X","authenticated-orcid":false,"given":"Evan D.","family":"Kharasch","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Duke University School of Medicine  Durham North Carolina USA"},{"name":"Bermaride LLC  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2019.03.029"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2020.04.004"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1811"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01876-7"},{"key":"e_1_2_8_5_1","volume-title":"Federal Regulation of methadone treatment","author":"Rettig A.","year":"1995"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.24m15438"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00406-023-01571-4"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100120"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2717"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000867"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1405"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3182423478"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2004.02079.x"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2014.10.014"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinane.2024.111572"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000005210"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:JOPA.0000012998.04442.1f"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1570-0232(04)00541-0"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9112-5"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00760-6"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200241140-00003"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12687"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.115.064352"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.5414\/CPP38035"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1990.37"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1981.34"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015884102663"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/1520-636X(2000)12:9<681::AID-CHIR7>3.0.CO;2-J"},{"key":"e_1_2_8_30_1","first-page":"183","article-title":"Opioid chronopharmacology: influence of timing of infusion on fentanyl\u2019s analgesic efficacy in healthy human volunteers","volume":"3","author":"Boom M.","year":"2010","journal-title":"J. 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