{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:49:18Z","timestamp":1776127758928,"version":"3.50.1"},"reference-count":22,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2018R1A6A1A03025108;  2019R1F1A1052243"],"award-info":[{"award-number":["2018R1A6A1A03025108;  2019R1F1A1052243"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002648","name":"The Catholic University of Korea","doi-asserted-by":"publisher","award":["Research Fund, 2020"],"award-info":[{"award-number":["Research Fund, 2020"]}],"id":[{"id":"10.13039\/501100002648","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>DA-6886 is a novel serotonin (5-hydroxytrypamine [5-HT]) receptor 4 agonist for the potential treatment of constipation-predominant irritable bowel syndrome. The purpose of this study was to validate the quantitative assay of DA-6886 in rat plasma and to evaluate the pharmacokinetics and tissue distribution of DA-6886 in rats. The liquid chromatography\u2013tandem mass spectrometry (LC\u2013MS\/MS) method for the robust quantification of DA-6886 in rat plasma was successfully validated and applied to the pharmacokinetic studies in rats. The pharmacokinetic parameters of DA-6886 in rats were evaluated following single intravenous or oral administration at three dose levels (2, 10, and 20 mg\/kg). DA-6886 exhibited a smaller dose-normalized area under the plasma concentration\u2013time curve (AUC) values and faster clearances in the low-dose group than in the high-dose group following both intravenous and oral administration. The steady-state volume of distribution (Vss) of DA-6886 was relatively large (4.91\u20137.84 L\/kg), which was consistent with its high distribution to the liver, kidney, lung, and digestive tract, and was dose-independent. After oral administration, the extent of absolute bioavailability (F) tended to increase (18.9\u201355.0%) with an increasing dose. The slope of the log-transformed AUC and\/or Cmax values versus log dose was greater than unity and greater for oral administration (~1.9) than for intravenous administration (~1.1). Because the nonlinear pharmacokinetics of DA-6886 was more obviously observed after oral administration, it appears that the saturation of pre-systemic intestinal and\/or hepatic first-pass extraction of DA-6886 at high doses occurred.<\/jats:p>","DOI":"10.3390\/pharmaceutics14040702","type":"journal-article","created":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T21:29:36Z","timestamp":1648416576000},"page":"702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacokinetics of DA-6886, A New 5-HT4 Receptor Agonist, in Rats"],"prefix":"10.3390","volume":"14","author":[{"given":"Dae Young","family":"Lee","sequence":"first","affiliation":[{"name":"Research Center, Dong-A ST Co., Ltd., Yongin 17073, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9906-5212","authenticated-orcid":false,"given":"Hee Eun","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e14125","DOI":"10.1111\/nmo.14125","article-title":"Colonic 5-HT4 receptors are targets for novel prokinetic drugs","volume":"33","author":"Galligan","year":"2021","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1517\/13543784.2010.482927","article-title":"New-generation 5-HT4 receptor agonists: Potential for treatment of gastrointestinal motility disorders","volume":"19","author":"Manabe","year":"2010","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/j.1365-2036.2012.05011.x","article-title":"Systematic review: Cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders","volume":"35","author":"Tack","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/apt.12571","article-title":"Systematic review with meta-analysis: Highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation","volume":"39","author":"Shin","year":"2014","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.apsb.2015.05.006","article-title":"Current developments in pharmacological therapeutics for chronic constipation","volume":"5","author":"Jiang","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_6","first-page":"93","article-title":"Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors","volume":"288","author":"Jin","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/S0016-5085(98)70203-3","article-title":"5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine","volume":"115","author":"Grider","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6593","DOI":"10.3748\/wjg.v23.i36.6593","article-title":"New therapeutic perspectives in irritable bowel syndrome: Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond","volume":"23","author":"Sinagra","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ejphar.2014.03.061","article-title":"Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice","volume":"735","author":"Lee","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S357","DOI":"10.1016\/S0016-5085(14)61293-2","article-title":"Effects of DA-6886 on colonic motility in conscious guinea pigs","volume":"146","author":"Moon","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_11","unstructured":"National Library of Medicine (U.S.) (2022, February 22). Phase I Clinical Trial of DA-6886 in Healthy Male Subjects. Identifier NCT01633723. (2012, August\u20132014, April), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/record\/NCT01633723."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4327","DOI":"10.1002\/jps.21702","article-title":"Pharmacokinetics of liquiritigenin in mice, rats, rabbits, and dogs, and animal scale-up","volume":"98","author":"Kang","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kwon, M.H., Lee, D.Y., and Kang, H.E. (2021). Development and Validation of an LC-MS\/MS Method for Quantification of the Novel Antibacterial Candidate DA-7010 in Plasma and Application to a Preclinical Pharmacokinetic Study. Pharmaceuticals, 14.","DOI":"10.3390\/ph14020163"},{"key":"ref_14","unstructured":"Bioanalytical Method Validation Guidance for Industry (2021, December 08). US FDA\/Center for Drug Evaluation and Research, Available online: https:\/\/www.fda.gov\/media\/70858\/download."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gibaldi, M., and Perrier, D. (1982). Pharmacokinetics, Marcel-Dekker. [2nd ed.].","DOI":"10.1201\/b14095"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/BF01062108","article-title":"Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve","volume":"6","author":"Chiou","year":"1978","journal-title":"J. Pharmacokinet. BioPharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1023\/A:1026451721686","article-title":"Confidence interval criteria for assessment of dose proportionality","volume":"17","author":"Smith","year":"2000","journal-title":"Pharm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1002\/pst.326","article-title":"Exploratory assessment of dose proportionality: Review of current approaches and proposal for a practical criterion","volume":"8","author":"Hummel","year":"2009","journal-title":"Pharm. Stat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1016\/j.xphs.2017.04.052","article-title":"Analysis of Nonlinear Pharmacokinetics of a Highly Albumin-Bound Compound: Contribution of Albumin-Mediated Hepatic Uptake Mechanism","volume":"106","author":"Fukuchi","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1124\/dmd.119.089151","article-title":"Assessment and Confirmation of Species Difference in Nonlinear Pharmacokinetics of Atipamezole with Physiologically Based Pharmacokinetic Modeling","volume":"48","author":"Li","year":"2020","journal-title":"Drug Metab. Dispos."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1023\/A:1018943613122","article-title":"Physiological parameters in laboratory animals and humans","volume":"10","author":"Davies","year":"1993","journal-title":"Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.jpba.2016.08.030","article-title":"Pharmacokinetics and tissue distribution study of prucalopride in rats by ultra high performance liquid chromatography with tandem mass spectrometry","volume":"131","author":"Zuo","year":"2016","journal-title":"J. Pharm. Biomed. Anal."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/4\/702\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:43:42Z","timestamp":1760136222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/4\/702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":22,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["pharmaceutics14040702"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14040702","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]}}}