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To enhance both oral bioavailability and brain penetration, three formulations of <jats:sc>l<\/jats:sc>\u2010THP suspension, mixture of <jats:sc>l<\/jats:sc>\u2010THP\u2013puerarin and self\u2010microemulsifying drug delivery systems (SMEDDS) were prepared. A sensitive and reliable ultra\u2010high\u2010performance liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of <jats:sc>l<\/jats:sc>\u2010THP and its active metabolite <jats:sc>l<\/jats:sc>\u2010isocorypalmine (<jats:sc>l<\/jats:sc>\u2010ICP) in rat brain. Diazepam was used as the internal standard. The chromatographic separation was achieved on a Bonshell ASB C<jats:sub>18<\/jats:sub> column at 30\u00b0C using acetonitrile\u2013aqueous formic acid as mobile phase in gradient mode. The linearity was validated over the concentration ranges of 4.00\u20132,500\u2009ng\/ml for <jats:sc>l<\/jats:sc>\u2010THP and 0.400\u2013500\u2009ng\/ml for <jats:sc>l<\/jats:sc>\u2010ICP. Full method validation was within the acceptance limits. The method was successfully used to determine the pharmacokinetics of two analytes following oral administration of these three formulations to rats. A significant difference was observed in the main pharmacokinetic parameters between SMEDDS and the suspension, and a 3.25\u2010 and 2.97\u2010fold increase in the relative bioavailability of <jats:sc>l<\/jats:sc>\u2010THP and <jats:sc>l<\/jats:sc>\u2010ICP, respectively, was observed with the SMEDDS compared with the suspension formulation. It was concluded that SMEDDS enhanced the absorption of <jats:sc>l<\/jats:sc>\u2010THP and <jats:sc>l<\/jats:sc>\u2010ICP and delayed their release in brain.<\/jats:p>","DOI":"10.1002\/bmc.5066","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T21:42:30Z","timestamp":1610746950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pharmacokinetic study of three different formulations of <scp>l<\/scp>\u2010tetrahydropalmatine in brain tissues of rats"],"prefix":"10.1002","volume":"35","author":[{"given":"Yiran","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmacy Shenyang Pharmaceutical University  Shenyang Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shenyang Pharmaceutical University  Shenyang Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Huai","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shenyang Pharmaceutical University  Shenyang Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congcong","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shenyang Pharmaceutical University  Shenyang Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shenyang Pharmaceutical University  Shenyang Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shenyang Pharmaceutical University  Shenyang Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8145-6303","authenticated-orcid":false,"given":"Ronghua","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shenyang Pharmaceutical University  Shenyang Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.3850"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21040456"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-011-0045-x"},{"issue":"3","key":"e_1_2_9_5_1","first-page":"539","article-title":"Regulation of puerarin on endorphin and dopamine in brain of rats with acute alcoholism","volume":"39","author":"Cui S. 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