title: Chiral on-line solid phase extraction coupled to liquid chromatography-tandem mass spectrometry assay for quantification of (R) and (S) enantiomers of methadone and its main metabolite in plasma.
abstract: The authors aimed at developing a liquid chromatography tandem mass spectrometry (LC-MS/MS) method with online extraction to determine (R)- and (S)- methadone enantiomers and its main metabolite 2-ethylidine-1,5-dimethyl-3,3 diphenylpyrrolidine (EDDP) in plasma. The analysis combined straightforward sample preparation, consisting of protein precipitation with acetonitrile, and an online enrichment by a flush/back-flush cycle before the second dimension chromatography. Using D3-deuterated internal standards allows overcoming significant relative matrix effect. Our method was linear up to 2000 ng/mL. This simple sample preparation provides sensitive (the limit of quantitation is 25 ng/mL for (R,S)-methadone and EDDP and 12.5 ng/mL for (R)- and (S)- methadone), accurate and precise (the intra-day and inter-day imprecision and inaccuracy are lower than 15%) quantification of the plasma concentration of these drugs. We have developed a reliable LC-MS/MS method for both routine therapeutic drug monitoring and pharmacokinetics studies and for toxicology analysis in the setting of methadone treatment or intoxication.
authors.affiliation: Assistant Professor, Clinical Pharmacology Department, and EA 4275 Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, Laboratoire de Pharmacologie clinique, Hôtel Dieu, 9 Quai Moncousu, 44093 Nantes Cedex, France. Electronic address: regis.bouquie@chu-nantes.fr.
authors.forename: Régis
authors.initials: R
authors.lastname: Bouquié
authors.affiliation: Practitioner, Clinical Pharmacology Department, Nantes University Hospital, France.
authors.lastname: Hélène Hernando
authors.affiliation: Practitioner, Clinical Pharmacology Department, Nantes University Hospital, France.
authors.lastname: Guillaume Deslandes
authors.affiliation: Technician, Clinical Pharmacology Department, Nantes University Hospital, France.
authors.forename: Amina Ben
authors.initials: AB
authors.lastname: Mostefa Daho
authors.affiliation: Engineer, Clinical Pharmacology Department, Nantes University Hospital, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Renaud
authors.affiliation: Practitioner, Department of Addictology and Psychiatry, Nantes University Hospital, France, and EA 4275 Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Grall-Bronnec
authors.affiliation: Professor in Pharmacology, Clinical Pharmacology Department, and EA 4275 Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, Nantes University Hospital, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Dailly
authors.affiliation: Professor in Clinical Pharmacology, Clinical Pharmacology Department, and EA 4275 Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, Nantes University Hospital, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Jolliet
mesh_terms: D002853:Chromatography, Liquid; D006801:Humans; D008691:Methadone / Q000097:blood*; D009294:Narcotics / Q000097:blood*; D011759:Pyrrolidines / Q000097:blood*; D052616:Solid Phase Extraction; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: D009294:Narcotics; D011759:Pyrrolidines; D008691:Methadone; C010724:2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
keywords: EDDP; Mass spectrometry; Methadone enantiomers; Method validation; Therapeutic drug monitoring