title: Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction.
abstract: To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.
authors.affiliation: Center of Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, United States.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Health Science Center, University of North Texas, Fort Worth, TX 76107, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Jann
authors.affiliation: Midwestern University, Institute for Healthcare Innovation, Glendale, AZ 85308, United States.
authors.forename: Chad
authors.initials: C
authors.lastname: Vandenberg
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Lausanne University, Hospital of Cery, Prilly, Lausanne, Switzerland.
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
authors.affiliation: Center of Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, United States. Electronic address: chesas@langate.gsu.edu.
authors.forename: Shahab A
authors.initials: SA
authors.lastname: Shamsi
mesh_terms: D002138:Calibration; D020374:Chromatography, Micellar Electrokinetic Capillary / Q000379:methods*; D000069468:Desvenlafaxine Succinate / Q000097:blood / Q000302:isolation & purification*; D004347:Drug Interactions; D019075:Electrophoresis, Capillary / Q000379:methods; D006678:HIV / Q000502:physiology; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D057230:Limit of Detection; D011108:Polymers / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods*; D000069470:Venlafaxine Hydrochloride / Q000097:blood / Q000302:isolation & purification*
chemical_list: D017320:HIV Protease Inhibitors; D011108:Polymers; D019469:Indinavir; D000069470:Venlafaxine Hydrochloride; D000069468:Desvenlafaxine Succinate
keywords: Enantioseparation; MKEC-ESI-MS/MS; Poly-L,L-SULA; Venlafaxine/O-desmethylvenlafaxine