{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T23:46:10Z","timestamp":1789688770051,"version":"4.0.1"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Cannabidiol is a novel antiseizure medication approved in Europe and the US for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex. We describe in this article a new and simple liquid chromatography-mass spectrometry method (LC-MS\/MS) for the determination of cannabidiol and its active metabolite 7-hydroxy-cannabidiol in microvolumes of serum and saliva (50\u00a0\u03bcl), to be used as a tool for therapeutic drug monitoring (TDM) and pharmacokinetic studies. After on-line solid phase extraction cannabidiol, 7-hydroxy-cannabidiol and the internal standard cannabidiol-<jats:italic>d3<\/jats:italic> are separated on a monolithic C18 column under gradient conditions. Calibration curves are linear within the validated concentration range (10\u20131,000\u00a0ng\/ml for cannabidiol and 5\u2013500\u00a0ng\/ml for 7-hydroxy-cannabidiol). The method is accurate (intraday and interday accuracy within 94\u2013112% for cannabidiol, 91\u2013109% for 7-hydroxy-cannabidiol), precise (intraday and interday precision &amp;lt;11.6% for cannabidiol and &amp;lt;11.7% for 7- hydroxy-cannabidiol) and sensitive, with a LOQ of 2.5\u00a0ng\/ml for cannabidiol and 5\u00a0ng\/ml for 7-hydroxy-cannabidiol. The stability of the analytes was confirmed under different storage conditions. Extraction recoveries were in the range of 81\u2013129% for cannabidiol and 100\u2013113% for 7-hydroxy-cannabidiol. The applicability of the method to TDM was demonstrated by analysis of human serum and saliva samples obtained from patients with epilepsy treated with cannabidiol.<\/jats:p>","DOI":"10.3389\/fphar.2022.915004","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T07:05:45Z","timestamp":1655881545000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["On-Line Solid Phase Extraction High Performance Liquid Chromatography Method Coupled With Tandem Mass Spectrometry for the Therapeutic Monitoring of Cannabidiol and 7-Hydroxy-cannabidiol in Human Serum and Saliva"],"prefix":"10.3389","volume":"13","author":[{"given":"Valentina","family":"Franco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Palmisani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Marchiselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Crema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Fattore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"De Giorgis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Varesio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Rota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenza Flora","family":"Dibari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Perucca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1111\/epi.14555","article-title":"Progress Report on New Antiepileptic Drugs: A Summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in More Advanced Clinical Development","volume":"59","author":"Bialer","year":"2018","journal-title":"Epilepsia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"462345","DOI":"10.1016\/j.chroma.2021.462345","article-title":"Identification and Quantification of Cannabinoids in Postmortem Fluids and Tissues by Liquid Chromatography-Tandem Mass Spectrometry","volume":"1652","author":"Cliburn","year":"2021","journal-title":"J. Chromatogr. A"},{"key":"B3","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1093\/jat\/bkaa164","article-title":"Determination and Distribution of Cannabinoids in Nail and Hair Samples","volume":"45","author":"Cobo-Golpe","year":"2021","journal-title":"J. Anal. Toxicol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e4952","DOI":"10.1002\/bmc.4952","article-title":"Determination of Cannabinoids in Plasma Using Salting-Out-Assisted Liquid-Liquid Extraction Followed by LC-MS\/MS Analysis","volume":"34","author":"da Silva","year":"2020","journal-title":"Biomed. Chromatogr."},{"key":"B5","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1002\/dta.1753","article-title":"Quantification of Six Cannabinoids and Metabolites in Oral Fluid by Liquid Chromatography-Tandem Mass Spectrometry","volume":"7","author":"Desrosiers","year":"2015","journal-title":"Drug Test. Anal."},{"key":"B6","volume-title":"Summary of Product Characteristics","year":"2019"},{"key":"B10","volume-title":"Full Prescribing Information","year":"2020"},{"key":"B7","volume-title":"Committee for Medicinal Products for Human Use: Guideline on Bioanalytical Method Validation","year":"2011"},{"key":"B8","doi-asserted-by":"publisher","first-page":"108442","DOI":"10.1016\/j.neuropharm.2020.108442","article-title":"Cannabidiol in the Treatment of Epilepsy: Current Evidence and Perspectives for Further Research","volume":"185","author":"Franco","year":"2021","journal-title":"Neuropharmacology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1007\/s40265-019-01171-4","article-title":"Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy","volume":"79","author":"Franco","year":"2019","journal-title":"Drugs"},{"key":"B11","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.lfs.2011.05.018","article-title":"Identification of Cytochrome P450 Enzymes Responsible for Metabolism of Cannabidiol by Human Liver Microsomes","volume":"89","author":"Jiang","year":"2011","journal-title":"Life Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"630","DOI":"10.3390\/ph14070630","article-title":"UHPLC-MS\/MS Analysis of Cannabidiol and its Metabolites in Serum of Patients with Resistant Epilepsy Treated with CBD Formulations","volume":"14","author":"Malaca","year":"2021","journal-title":"Pharmaceuticals"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1124\/dmd.109.026898","article-title":"Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids","volume":"37","author":"Mazur","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1002\/cpdd.665","article-title":"A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects","volume":"8","author":"Morrison","year":"2019","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1111\/j.1528-1167.2008.01561.x","article-title":"Antiepileptic Drugs-Best Practice Guidelines for Therapeutic Drug Monitoring: a Position Paper by the Subcommission on Therapeutic Drug Monitoring, ILAE Commission on Therapeutic Strategies","volume":"49","author":"Patsalos","year":"2008","journal-title":"Epilepsia"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1097\/FTD.0b013e31827c11e7","article-title":"Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva","volume":"35","author":"Patsalos","year":"2013","journal-title":"Ther. Drug Monit."},{"key":"B17","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1097\/FTD.0000000000000846","article-title":"An Ultrafast Ultrahigh-Performance Liquid Chromatography Coupled with Tandem Mass Spectrometry Method for Cannabidiol Monitoring in Pediatric Refractory Epilepsy","volume":"43","author":"P\u00e9rez Montilla","year":"2021","journal-title":"Ther. Drug Monit."},{"key":"B18","doi-asserted-by":"publisher","first-page":"61","DOI":"10.14581\/jer.17012","article-title":"Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?","volume":"7","author":"Perucca","year":"2017","journal-title":"J. Epilepsy Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.clinbiochem.2021.09.005","article-title":"Screening and Confirmation Methods for the Qualitative Identification of Nine Phytocannabinoids in Urine by LC-MS\/MS","volume":"98","author":"Reber","year":"2021","journal-title":"Clin. Biochem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1093\/jat\/bkaa142","article-title":"Detection of Cannabinoids by LC-MS-MS and ELISA in Breast Milk","volume":"45","author":"Sempio","year":"","journal-title":"J. Anal. Toxicol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1093\/jat\/bkab030","article-title":"Simultaneous Quantification of 17 Cannabinoids by LC-MS-MS in Human Plasma","volume":"46","author":"Sempio","year":"","journal-title":"J. Anal. Toxicol. Bkab030."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1007\/s40263-018-0578-5","article-title":"A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects","volume":"32","author":"Taylor","year":"2018","journal-title":"CNS Drugs"},{"key":"B23","doi-asserted-by":"publisher","first-page":"206","DOI":"10.2174\/1389200217666151210142051","article-title":"Cannabinoids and Cytochrome P450 Interactions","volume":"17","author":"Zendulka","year":"2016","journal-title":"Curr. Drug Metab."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.915004\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T07:05:51Z","timestamp":1655881551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.915004\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":23,"alternative-id":["10.3389\/fphar.2022.915004"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.915004","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]},"article-number":"915004"}}