TY - JOUR
T1 - 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
AU - Tittarelli, Roberta
AU - Pichini, Simona
AU - Pedersen, Daniel S
AU - Pacifici, Roberta
AU - Moresco, Monica
AU - Pizza, Fabio
AU - Busardò, Francesco Paolo
AU - Plazzi, Giuseppe
N1 - Copyright © 2017 Elsevier B.V. All rights reserved.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1016/j.forsciint.2017.01.015
DO - 10.1016/j.forsciint.2017.01.015
M3 - Journal article
C2 - 28139340
SN - 0379-0738
VL - 274
SP - 70
EP - 74
JO - Forensic Science International
JF - Forensic Science International
ER -