title: Ultra-high-performance liquid chromatography tandem mass spectrometry determination of GHB, GHB-glucuronide in plasma and cerebrospinal fluid of narcoleptic patients under sodium oxybate treatment.
abstract: Sodium oxybate (Xyrem®), the sodium salt of γ- hydroxybutyric acid (GHB), is a first-line treatment of the symptoms induced by type 1 narcolepsy (NT1) and it is highly effective in improving sleep architecture, decreasing excessive daytime sleepiness and the frequency of cataplexy attacks. Using an ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) validated method, GHB was determined together with its glucuronide (GHB-gluc), in plasma and cerebrospinal fluid (CSF) samples of NT1 patients under sodium oxybate treatment. To characterize the plasma pharmacokinetics of GHB, three subjects with NT1 were administered at time 0 and 4h with 1.25, 1.5 and 3.55g Xyrem®, respectively and had their blood samples collected at 7 time points throughout an 8-h session. CSF specimens, collected for orexin A measurement from the same three subjects 6h after their second administration, were also tested. The results obtained suggested that GHB plasma values increased disproportionally with the rising doses, (Cmax0-4: 12.53, 32.95 and 69.62μg/mL; Cmax4-8: 44.93, 75.03 and 111.93μg/mL for total Xyrem®dose of 2.5, 3 and 7g respectively) indicating non-linear dose-response. GHB-Gluc was present only in traces in all plasma samples from treated patients, not changing with increasing Xyrem®doses. GHB values of 5.62, 6.10 and 17.74μg/mL for 2, 3 and 7g Xyrem®were found in CSF with a significant difference from control values. GHB-Gluc was found in negligible concentrations with no differences to those of control individuals. In conclusion this simple and fast UHPLC-MS/MS method proved useful for pharmacokinetic studies and therapeutic drug monitoring of GHB in narcoleptic patients treated with sodium oxybate.
authors.affiliation: Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Tittarelli
authors.affiliation: Drug Abuse and Doping Unit, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pichini
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pedersen
authors.affiliation: Drug Abuse and Doping Unit, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Pacifici
authors.affiliation: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Moresco
authors.affiliation: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, AUSL di Bologna, Bologna, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pizza
authors.affiliation: Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy. Electronic address: fra.busardo@libero.it.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Busardò
authors.affiliation: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, AUSL di Bologna, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Plazzi
mesh_terms: D000293:Adolescent; D000328:Adult; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000097:blood* / Q000134:cerebrospinal fluid*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000097:blood* / Q000134:cerebrospinal fluid*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000188:drug therapy; D012978:Sodium Oxybate / Q000008:administration & dosage / Q000097:blood* / Q000134:cerebrospinal fluid*; D053719:Tandem Mass Spectrometry
chemical_list: D002492:Central Nervous System Depressants; D020719:Glucuronides; D012978:Sodium Oxybate
keywords: Cerebrospinal fluid; GHB; GHB glucuronide; Narcolepsy; Plasma pharmacokinetics; Ultra-high performance liquid chromatography tandem mass spectrometry