{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:05:21Z","timestamp":1789700721806,"version":"4.0.1"},"reference-count":19,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Alverine is an antispasmodic agent characterized by extensive metabolism, and systemic exposure is largely driven by its metabolites. However, conventional parent\u2013metabolite pharmacokinetic models typically assume metabolite formation solely from the systemic parent compound, which may not adequately capture route\u2010dependent differences in metabolite exposure. This study aimed to develop an integrated parent\u2013metabolite pharmacokinetic model to simultaneously describe alverine and its three major metabolites (M1, M2, and M3) in mice following intravenous (IV) and per\u2010oral (PO) administration. Plasma concentration\u2013time data were analyzed using a stepwise nonlinear mixed\u2010effects model. Alternative structural models were evaluated to account for route\u2010dependent metabolite appearance. Distinct route\u2010dependent differences were observed in alverine metabolite exposure, with substantially higher levels following PO administration, particularly for M2, despite limited parent exposure. A model without presystemic metabolism, which assumed parent\u2010derived formation alone, failed to adequately describe these data, leading to an overprediction of early parent concentrations. The final model incorporated presystemic metabolism for M1 and M3, significantly improving model fit (\u0394OFV\u2009=\u2009\u2212138.10) and providing an adequate description of both parent and metabolite profiles across routes. These findings suggest that systemic metabolite exposure following oral dosing is strongly influenced by presystemic processes that cannot be captured by parent\u2010driven formation alone. The proposed model provides a parsimonious structural framework to account for these effects without requiring detailed mechanistic information. This approach may be broadly applicable to compounds exhibiting metabolite\u2010dominant exposure and highlights the importance of flexible structural models in pharmacometric analyses of route\u2010dependent pharmacokinetics.<\/jats:p>","DOI":"10.1002\/psp4.70342","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:34:20Z","timestamp":1789187660000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of Integrated Parent\u2013Metabolite Pharmacokinetic Model With Apparent Presystemic Metabolism to Characterize the Disposition of Alverine"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6244-4106","authenticated-orcid":false,"given":"Ara","family":"Cho","sequence":"first","affiliation":[{"name":"Advanced Alternative Testing Team Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"},{"name":"Korea Preclinical Evaluation Center Korea Research Institute of Bioscience and Biotechnology  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon\u2010Cheol","family":"Jeong","sequence":"additional","affiliation":[{"name":"Advanced Alternative Testing Team Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"},{"name":"Korea Preclinical Evaluation Center Korea Research Institute of Bioscience and Biotechnology  Daejeon Republic of Korea"},{"name":"Laboratory Animal Resource &amp; Research Center Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MinJu","family":"Kim","sequence":"additional","affiliation":[{"name":"Advanced Alternative Testing Team Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inkyung","family":"Cho","sequence":"additional","affiliation":[{"name":"Advanced Alternative Testing Team Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon\u2010Jeong","family":"Na","sequence":"additional","affiliation":[{"name":"Advanced Alternative Testing Team Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"},{"name":"Korea Preclinical Evaluation Center Korea Research Institute of Bioscience and Biotechnology  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyong\u2010Cheol","family":"Ko","sequence":"additional","affiliation":[{"name":"Korea Preclinical Evaluation Center Korea Research Institute of Bioscience and Biotechnology  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon\u2010Jee","family":"Chae","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine Konyang University  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2175-8876","authenticated-orcid":false,"given":"Kyeong\u2010Ryoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Advanced Alternative Testing Team Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"},{"name":"Korea Preclinical Evaluation Center Korea Research Institute of Bioscience and Biotechnology  Daejeon Republic of Korea"},{"name":"Laboratory Animal Resource &amp; Research Center Korea Research Institute of Bioscience and Biotechnology  Cheongju Republic of Korea"},{"name":"Department of Bioengineering University of Science and Technology  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"(emc) E.M.C \u201cAlverine Citrate 60 mg Hard Capsules \u2013 Summary of Product Characteristics \u201davailable from https:\/\/www.medicines.org.uk\/emc\/product\/11541\/smpc?utm_source2026\u201004\u201002."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707496"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.620451"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/109414"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpha.2016.11.003"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2010.497487"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9282-9"},{"key":"e_1_2_10_9_1","volume-title":"Clinical Pharmacokinetics and Pharmacodynamics","author":"Rowland M.","year":"2010"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15010045"},{"key":"e_1_2_10_11_1","first-page":"4273","volume-title":"The Importance of PK\u2013PD","author":"Barrow J. 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