Jamalapuram Seshulatha, Vuppala Pradeep Kumar, Abdelazeem Ahmed H, McCurdy Christopher R, Avery Bonnie A
The University of Mississippi, Department of Pharmaceutics, University of Mississippi, Mississippi, USA.
Biomed Chromatogr. 2013 Aug;27(8):1034-40. doi: 10.1002/bmc.2901. Epub 2013 Apr 5.
Methamphetamine abuse continues as a major problem in the USA owing to its powerful psychological addictive properties. AZ66, 3-[4-(4-cyclohexylpiperazine-1-yl)pentyl]-6-fluorobenzo[d]thiazole-2(3H)-one, an optimized sigma receptor ligand, is a promising therapeutic agent against methamphetamine. To study the in vivo pharmacokinetics of this novel sigma receptor ligand in rats, a sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed in rat plasma and validated. The developed method requires a small volume of plasma (100 μL) and a simple liquid-liquid extraction. The chromatographic separations were achieved in 3.3 min using an Acquity UPLC BEH Shield RP18 column. The mass spectrophotometric detection was carried out using a Waters Micromass Quattro MicroTM triple-quadrupole system. Multiple reaction monitoring was used for the quantitation with transitions m/z 406 → m/z 181 for AZ66 and m/z 448 → m/z 285 for aripiprazole. The method was validated over a concentration range of 1-3500 ng/mL and the lower limit of quantitation was determined to be 1 ng/mL. Validation of the assay demonstrated that the developed UPLC/MS/MS method was sensitive, accurate and selective for the determination of AZ66 in rat plasma. The present method has been successfully applied to an i.v. pharmacokinetic study in Sprague-Dawley rats.
由于甲基苯丙胺具有强大的心理成瘾特性，其滥用在美国仍然是一个主要问题。AZ66，即3-[4-(4-环己基哌嗪-1-基)戊基]-6-氟苯并[d]噻唑-2(3H)-酮，一种优化的σ受体配体，是一种有前景的抗甲基苯丙胺治疗药物。为了研究这种新型σ受体配体在大鼠体内的药代动力学，建立并验证了一种用于大鼠血浆的灵敏超高效液相色谱/串联质谱（UPLC/MS/MS）方法。所建立的方法需要少量血浆（100μL）和简单的液-液萃取。使用Acquity UPLC BEH Shield RP18柱在3.3分钟内实现了色谱分离。使用Waters Micromass Quattro MicroTM三重四极杆系统进行质谱检测。采用多反应监测进行定量分析，AZ66的跃迁为m/z 406 → m/z 181，阿立哌唑的跃迁为m/z 448 → m/z 285。该方法在1-3500 ng/mL的浓度范围内进行了验证，定量下限确定为1 ng/mL。该分析方法的验证表明，所建立的UPLC/MS/MS方法对大鼠血浆中AZ66的测定具有灵敏性、准确性和选择性。本方法已成功应用于Sprague-Dawley大鼠的静脉药代动力学研究。
