{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:32:43Z","timestamp":1786627963395,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003654","name":"Korea Environmental Industry and Technology Institute","doi-asserted-by":"publisher","award":["RS-2022-KE002026"],"award-info":[{"award-number":["RS-2022-KE002026"]}],"id":[{"id":"10.13039\/501100003654","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2022-KE002026"],"award-info":[{"award-number":["RS-2022-KE002026"]}],"id":[{"id":"https:\/\/ror.org\/022r1q746","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Di(2-ethylhexyl) adipate (DEHA), a biocompatible ester plasticizer, has gained interest as a potential pharmaceutical excipient, yet its pharmacokinetics remain poorly characterized. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), in rats by integrating in vitro, in vivo, in silico, and physiological data. Methods: In vitro hydrolysis was evaluated across tissues using bis-(p-nitrophenyl) phosphate (BNPP) to distinguish BNPP-sensitive and -insensitive metabolism, and tissue-specific clearances were extrapolated to the whole body using a circulatory topology-based framework accounting for sequential extraction across tissues, venous blood, and lungs. Results: Both adipates underwent rapid BNPP-sensitive hydrolysis across multiple tissues, whereas DEHA additionally exhibited BNPP-insensitive metabolism. The framework yielded reasonable estimates of the observed arterial clearance in vivo. Following oral administration, DEHA showed a reproducible double-peak plasma profile, with lymphatic transport identified as the predominant absorption route responsible for the prolonged terminal phase. The final model adequately reproduced the plasma and mesenteric lymph concentration-time profiles of DEHA and MEHA following both intravenous and oral administration. Conclusions: By integrating multi-tissue metabolism, circulatory topology, and lymphatic absorption, this study provides a quantitative framework applicable to rapidly hydrolyzed, highly lipophilic ester compounds, including pharmaceutical excipients and ester prodrugs.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081001","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:47:11Z","timestamp":1786625231000},"page":"1001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiologically Based Pharmacokinetic Modeling of Di(2-ethylhexyl) Adipate and Its Primary Metabolite, Mono(2-ethylhexyl) Adipate, in Rats, Incorporating Circulatory Topology-Based Multi-Tissue Metabolism and Lymphatic Absorption"],"prefix":"10.3390","volume":"18","author":[{"given":"Eunsuk","family":"Yang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4190-6525","authenticated-orcid":false,"given":"Yoo-Seong","family":"Jeong","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4941-6113","authenticated-orcid":false,"given":"Minsang","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungchan","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk-Jae","family":"Chung","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","unstructured":"Research and Markets (2024). 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