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anti\u2013rheumatic drug derived from the Chinese medicinal plant Sinomenium acutum, demonstrates disease\u2013modifying properties but lacks comprehensive safety and toxicokinetic (TK) comparisons between physiological and pathological states. This study evaluated SH\u2019s safety profile, TK parameters, and intestinal absorption differences in adjuvant\u2013induced arthritis (AIA) and normal rats. Methods: Safety assessments determined median lethal doses (LD50) in female Sprague Dawley rats. TK parameters were analyzed via a validated ultrahigh performance liquid chromatography-tandem mass spectrometry approach after single oral administration of 600 mg\/kg SH. Plasma protein binding (PPB) were measured using equilibrium dialysis. Intestinal absorption was evaluated through everted gut sac experiments, with P\u2013glycoprotein (P\u2013gp) inhibition tested via verapamil co\u2013administration. Results: LD50 values revealed AIA rats tolerated SH better than normal rats (1179 vs. 805 mg\/kg). TK analysis showed that Cmax, AUC(0-t), and AUC(0-\u221e) of SIN in normal rats were 2.01, 1.94, and 2.14 times higher than in AIA rats, respectively, while CL\/F and V\/F in AIA rats were 2.24 times greater. In addition, the PPB of SIN in normal rats was 2 times greater than that in AIA rats. AIA rats exhibited significantly lower SH absorption in the jejunum and ileum compared to normal rats. Notably, verapamil co\u2013administration markedly increased SH absorption across most intestinal segments. Conclusions: Pathological states significantly alter SH\u2019s safety and TK profiles. Enhanced tolerance in AIA rats correlates with reduced intestinal absorption via altered P\u2013gp activity and decreased PPB. These findings emphasize the necessity of disease\u2013specific evaluations for optimizing SH\u2019s therapeutic safety in pathological contexts.<\/jats:p>","DOI":"10.3390\/pharmaceutics17040484","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T05:59:00Z","timestamp":1744091940000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Safety Profile, Toxicokinetic, and Intestinal Absorption Differences of a Naturally-Derived Anti-Rheumatic Drug, Sinomenine Hydrochloride, in Normal and Arthritic Rats"],"prefix":"10.3390","volume":"17","author":[{"given":"Yini","family":"He","sequence":"first","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gejing","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feichi","family":"Wu","sequence":"additional","affiliation":[{"name":"Hunan ZhenQin Pharmaceutical Group Co., Ltd., Huaihua 418000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianye","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4644-4451","authenticated-orcid":false,"given":"Xiong","family":"Cai","sequence":"additional","affiliation":[{"name":"Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, Y.S., Han, J.Y., Iqbal, O., and Liang, A.H. 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