Tittarelli Roberta, Pichini Simona, Pedersen Daniel S, Pacifici Roberta, Moresco Monica, Pizza Fabio, Busardò Francesco Paolo, Plazzi Giuseppe
Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy.
Drug Abuse and Doping Unit, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Forensic Sci Int. 2017 May;274:70-74. doi: 10.1016/j.forsciint.2017.01.015. Epub 2017 Jan 25.
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, (C: 12.53, 32.95 and 69.62μg/mL; C: 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.
羟丁酸钠（Xyrem），即γ-羟基丁酸（GHB）的钠盐，是1型发作性睡病（NT1）所致症状的一线治疗药物，在改善睡眠结构、减轻日间过度嗜睡及猝倒发作频率方面疗效显著。采用经过验证的超高效液相色谱串联质谱法（UHPLC-MS/MS），对接受羟丁酸钠治疗的NT1患者的血浆和脑脊液（CSF）样本中的GHB及其葡糖苷酸（GHB-葡糖）进行测定。为了描述GHB的血浆药代动力学特征，3名NT1受试者在0时和4小时分别服用1.25、1.5和3.55g Xyrem，并在8小时内的7个时间点采集血样。还对同一3名受试者在第二次给药6小时后采集的用于测定食欲素A的CSF样本进行了检测。所得结果表明，GHB血浆值随剂量增加呈不成比例的升高（总Xyrem剂量分别为2.5、3和7g时，C分别为12.53、32.95和69.62μg/mL；C分别为44.93、75.03和111.93μg/mL），表明存在非线性剂量反应。在接受治疗患者的所有血浆样本中，GHB-葡糖仅微量存在，且不随Xyrem剂量增加而变化。在CSF中，2、3和7g Xyrem的GHB值分别为5.62、6.10和17.74μg/mL，与对照值有显著差异。GHB-葡糖的浓度可忽略不计，与对照个体无差异。总之，这种简单快速的UHPLC-MS/MS方法被证明可用于发作性睡病患者接受羟丁酸钠治疗时GHB的药代动力学研究和治疗药物监测。
