{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:02:01Z","timestamp":1785420121660,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["82574314"],"award-info":[{"award-number":["82574314"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82574314"],"award-info":[{"award-number":["82574314"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Shandong Provincial Key Research and Development Program","doi-asserted-by":"publisher","award":["2023CXPT092"],"award-info":[{"award-number":["2023CXPT092"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>LY104 (previously designated as B7) is a selective phosphodiesterase 4 inhibitor with promising activity against chronic obstructive pulmonary disease. We previously reported its single-dose pharmacokinetics and tissue distribution in rats. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS\/MS) method was developed and validated for the simultaneous quantification of LY104 and its major metabolite M1 in rat plasma following ICH M10 guidelines. The method showed excellent linearity over 20\u20131200 ng\/mL for both analytes, with retention times of 2.85 min (LY104) and 3.22 min (M1). Using this method, we extended our previous work in several directions. Re-analysis of previously published single-dose pharmacokinetic and tissue distribution data revealed no significant sex differences for LY104. Newly generated multiple-dose studies (1 mg\/kg daily for 7 days) demonstrated no accumulation of LY104 or M1. The pharmacokinetic profile of M1 was quantified for the first time. Comprehensive in vitro investigations included plasma and liver microsomal stability, plasma protein binding, and excretion studies. This systematic preclinical pharmacokinetic characterization of LY104 and M1, incorporating re-analysis of existing data with sex stratification, newly generated multiple-dose and metabolite data, excretion studies, and comprehensive in vitro investigations, provides useful information to support further drug development and clinical trial design.<\/jats:p>","DOI":"10.3390\/md24060215","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T15:00:48Z","timestamp":1781535648000},"page":"215","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Pharmacokinetics of the Marine-Derived PDE4 Inhibitor LY104 and Its Major Metabolite M1 in Rats: A Validated LC-MS\/MS Method with Sex Comparison, Multiple-Dose, Protein Binding, Metabolic Stability, and Excretion Studies"],"prefix":"10.3390","volume":"24","author":[{"given":"Xiaochen","family":"Niu","sequence":"first","affiliation":[{"name":"Marine Biomedical Research Institute of Qingdao, Ocean University of China, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Marine Biomedical Research Institute of Qingdao, Ocean University of China, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deqi","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanhua","family":"Du","sequence":"additional","affiliation":[{"name":"Marine Biomedical Research Institute of Qingdao, Ocean University of China, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiejie","family":"Hao","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1223-618X","authenticated-orcid":false,"given":"Jianchun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Marine Biomedical Research Institute of Qingdao, Ocean University of China, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7635","DOI":"10.1038\/s41467-022-35253-x","article-title":"The establishment of COPD organoids to study host-pathogen interaction reveals enhanced viral fitness of SARS-CoV-2 in bronchi","volume":"13","author":"Chan","year":"2022","journal-title":"Nat. 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