George Rani, Lobb Michael, Haywood Alison, Khan Sohil, Hardy Janet, Good Phillip, Hennig Stefanie, Norris Ross
School of Pharmacy, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia.
Mater Pathology Services, South Brisbane, QLD, Australia.
Talanta. 2016;149:142-148. doi: 10.1016/j.talanta.2015.11.044. Epub 2015 Nov 19.
Methadone is a potent lipophilic synthetic opioid that is effective in the treatment of cancer pain and perceived benefit in difficult pain control scenarios (especially in cases of neuropathic pain). The use of methadone in clinical practice is challenging however, due to the narrow therapeutic window and large inter- and intra-individual variability in therapeutic response. Quantitation of the enantiomers d- and l-methadone (d- and l-MTD) in plasma and saliva provides a basis for studying its pharmacokinetics in patients with cancer and for monitoring efficacy, toxicity and side-effects. This assay involves quantitation of the enantiomers of methadone using their respective deuterated internal standards, in plasma and saliva matrices with no impact of ion suppression in either matrix. The analytical recoveries of d- and l-MTD from the saliva collection devices (Salivette®) are optimised in this novel method with an accurate and simple extraction method employing dichloromethane. Optimal enantioselective separations were achieved using an α1-acid glycoprotein chiral stationary phase and triple quadrupole tandem mass spectrometer. Linearity was demonstrated over 0.05-1000µg/L for both enantiomers in plasma and in saliva with correlation coefficients greater than 0.998. The lower limit of quantitation (LLOQ) was determined to be 0.1µg/L in plasma and saliva for d- and l-MTD. Accuracy of the method ranges from 100% to 106% even at the LLOQ and total precision, expressed as the coefficient of variation, was between 0.2% and 4.4% for both analytes in both matrices. A simple one step extraction procedure resulted in recoveries greater than 95% for both analytes, at concentrations as low as 0.5µg/L, from the Salivette®. The validated method was applied successfully in 14 paired plasma and saliva samples obtained from adult patients with cancer pain receiving methadone.
美沙酮是一种强效亲脂性合成阿片类药物，在治疗癌症疼痛方面有效，且在疼痛控制困难的情况下（尤其是神经性疼痛病例）被认为有益。然而，由于治疗窗狭窄以及治疗反应存在较大的个体间和个体内差异，美沙酮在临床实践中的使用具有挑战性。定量测定血浆和唾液中d-和l-美沙酮（d-和l-MTD）对映体，为研究其在癌症患者中的药代动力学以及监测疗效、毒性和副作用提供了依据。该测定方法涉及使用各自的氘代内标物对美沙酮对映体进行定量，在血浆和唾液基质中均不受离子抑制的影响。在这种新方法中，通过采用二氯甲烷的准确且简单的提取方法，优化了从唾液收集装置（Salivette®）中回收d-和l-MTD的分析回收率。使用α1-酸性糖蛋白手性固定相和三重四极杆串联质谱仪实现了最佳的对映体选择性分离。血浆和唾液中两种对映体在0.05 - 1000µg/L范围内均呈现线性，相关系数大于0.998。d-和l-MTD在血浆和唾液中的定量下限（LLOQ）均确定为0.1µg/L。即使在LLOQ水平，该方法的准确度范围为100%至106%，两种基质中两种分析物的总精密度（以变异系数表示）在0.2%至4.4%之间。一个简单的一步提取程序使得从Salivette®中回收两种分析物的回收率在浓度低至0.5µg/L时均大于95%。该经过验证的方法成功应用于从接受美沙酮治疗的成年癌症疼痛患者中获取的14对血浆和唾液样本。
