{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:08:04Z","timestamp":1740146884178,"version":"3.37.3"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T00:00:00Z","timestamp":1719273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003787","name":"Natural Science Foundation of Hebei Province","doi-asserted-by":"publisher","award":["H202106384"],"award-info":[{"award-number":["H202106384"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>N-butylphthalide (NBP) is a monomeric compound extracted from natural plant celery seeds, whether intestinal microbiota alteration can modify its pharmacokinetics is still unclear. The purpose of this study is to investigate the effect of intestinal microbiota alteration on the pharmacokinetics of NBP and its related mechanisms.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>After treatment with antibiotics and probiotics, plasma NBP concentrations in SD rats were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS\/MS). The effect of intestinal microbiota changes on NBP pharmacokinetics was compared. Intestinal microbiota changes after NBP treatment were analyzed by 16S rRNA sequencing. Expressions of CYP3A1 mRNA and protein in the liver and small intestine tissues under different intestinal flora conditions were determined by qRT-PCR and Western Blot. KEGG analysis was used to analyze the effect of intestinal microbiota changes on metabolic pathways.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Compared to the control group, the values of C<jats:sub>max<\/jats:sub>, AUC<jats:sub>0-8<\/jats:sub>, AUC<jats:sub>0-\u221e<\/jats:sub>, t<jats:sub>1\/2<\/jats:sub> in the antibiotic group increased by 56.1% (<jats:italic>P&lt;<\/jats:italic>0.001), 56.4% (<jats:italic>P&lt;<\/jats:italic>0.001), 53.2% (<jats:italic>P<\/jats:italic>&lt;0.001), and 24.4% (<jats:italic>P<\/jats:italic>&lt;0.05), respectively. In contrast, the CL and T<jats:sub>max<\/jats:sub> values decreased by 57.1% (<jats:italic>P&lt;<\/jats:italic>0.001) and 28.6% (<jats:italic>P<\/jats:italic>&lt;0.05), respectively. Treatment with antibiotics could reduce the richness and diversity of the intestinal microbiota. CYP3A1 mRNA and protein expressions in the small intestine of the antibiotic group were 61.2% and 66.1% of those of the control group, respectively. CYP3A1 mRNA and protein expressions in the liver were 44.6% and 63.9% of those in the control group, respectively. There was no significant change in the probiotic group. KEGG analysis showed that multiple metabolic pathways were significantly down-regulated in the antibiotic group. Among them, the pathways of drug metabolism, bile acid biosynthesis and decomposition, and fatty acid synthesis and decomposition were related to NBP biological metabolism.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Antibiotic treatment could affect the intestinal microbiota, decrease CYP3A1 mRNA and protein expressions and increase NBP exposure <jats:italic>in vivo<\/jats:italic> by inhibiting pathways related to NBP metabolism.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0297713","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T18:35:37Z","timestamp":1719340537000},"page":"e0297713","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antibiotics affect the pharmacokinetics of n-butylphthalide in vivo by altering the intestinal microbiota"],"prefix":"10.1371","volume":"19","author":[{"given":"Xiangchen","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feifei","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuling","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9306-3267","authenticated-orcid":true,"given":"Zhiqing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,6,25]]},"reference":[{"issue":"8","key":"pone.0297713.ref001","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1177\/0271678X18780130","article-title":"The gut microbiome primes a cerebroprotective immune response after stroke","volume":"38","author":"V Singh","year":"2018","journal-title":"J Cereb Blood Flow Metab"},{"issue":"6","key":"pone.0297713.ref002","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1161\/STROKEAHA.120.029262","article-title":"Distinct commensal bacterial signature in the gut is associated with acute and long-term protection from ischemic stroke","volume":"51","author":"C Benakis","year":"2020","journal-title":"Stroke"},{"issue":"5","key":"pone.0297713.ref003","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/nm.4068","article-title":"Commensal microbiota affects ischemic stroke outcome by regulating intestinal \u03b3\u03b4 T cells","volume":"22","author":"C Benakis","year":"2016","journal-title":"Nat Med"},{"issue":"7","key":"pone.0297713.ref004","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1002\/mdc3.12828","article-title":"The gut microbiome: A therapeutically targetable site of peripheral levodopa metabolism","volume":"6","author":"E Mulroy","year":"2019","journal-title":"Mov Disord Clin Pract"},{"issue":"5","key":"pone.0297713.ref005","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1124\/dmd.105.008672","article-title":"The human intestinal cytochrome P450 \"pie\"","volume":"34","author":"MF Paine","year":"2006","journal-title":"Drug Metab Dispos"},{"issue":"3","key":"pone.0297713.ref006","first-page":"1552","article-title":"Characterization of interintestinaland intraintestinal variations in human CYP3A-dependent metabolism","volume":"283","author":"MF Paine","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"issue":"7762","key":"pone.0297713.ref007","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/s41586-019-1291-3","article-title":"Mapping human microbiome drug metabolism by gut bacteria and their genes","volume":"570","author":"M Zimmermann","year":"2019","journal-title":"Nature"},{"issue":"3","key":"pone.0297713.ref008","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1097\/MOG.0000000000000057","article-title":"Bile acids and the gut microbiome","volume":"30","author":"JM Ridlon","year":"2014","journal-title":"Curr Opin Gastroenterol"},{"issue":"11","key":"pone.0297713.ref009","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.molmed.2015.09.001","article-title":"Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders","volume":"21","author":"S Fiorucci","year":"2015","journal-title":"Trends Mol. 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