Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA; Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Poznań, Poland.
Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St Louis, MO 63110, USA.
J Pharm Biomed Anal. 2023 Oct 25;235:115625. doi: 10.1016/j.jpba.2023.115625. Epub 2023 Aug 2.
Ondansetron is used in clinical settings as an antiemetic drug. Although the animal studies showed its potential effectiveness also in treating neuropathic pain, the results from humans are inconclusive. The lack of efficacy of ondansetron in a subset of patients might be due to the overexpression of P-glycoprotein, which could result in low concentrations of ondansetron in the central nervous system (CNS). A surrogate of the CNS exposure might be drug concentration in the cerebrospinal fluid (CSF), especially in humans, as assessing the drug disposition directly in the patient's brain would be challenging. The study aimed to develop a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine concentrations of ondansetron in human KEDTA plasma and CSF. Ondansetron was extracted from biological matrices by liquid-liquid extraction. The quantification was performed on a Sciex QTRAP 6500+ mass spectrometer with labeled ondansetron as an internal standard. The calibration range was 0.25-350 ng/mL in plasma and 0.025-100 ng/mL in CSF; for both matrices, 25 µL of samples was required for the assays. The method was validated according to the FDA and EMA guidelines and showed acceptable results. A pilot study confirmed its suitability for clinical samples: after 4-16 mg of intravenous ondansetron, the determined concentrations in plasma were 1.22-235.90 ng/mL, while in CSF - 0.018-11.93 ng/mL. In conclusion, the developed method fulfilled all validation requirements and can be applied to pharmacokinetic studies assessing the CNS ondansetron exposure in humans. The method's advantages, such as a low volume of matrix and a wide calibration range, support its use in a study in which rich sampling and various drug doses are expected.
昂丹司琼在临床上被用作止吐药物。尽管动物研究表明它在治疗神经性疼痛方面也有潜在的效果，但来自人类的结果尚无定论。昂丹司琼在一部分患者中无效的原因可能是 P-糖蛋白的过度表达，这可能导致中枢神经系统（CNS）中的昂丹司琼浓度较低。CNS 暴露的替代物可能是脑脊液（CSF）中的药物浓度，尤其是在人类中，因为直接在患者的大脑中评估药物分布会具有挑战性。本研究旨在开发一种灵敏的液相色谱-串联质谱（LC-MS/MS）方法，以测定人 KEDTA 血浆和 CSF 中昂丹司琼的浓度。昂丹司琼通过液-液萃取从生物基质中提取。定量分析采用 Sciex QTRAP 6500+质谱仪，以标记的昂丹司琼为内标。血浆中的校准范围为 0.25-350ng/mL，CSF 中的校准范围为 0.025-100ng/mL；两种基质的测定均需要 25µL 的样品。该方法按照 FDA 和 EMA 指南进行了验证，结果令人满意。一项初步研究证实了它对临床样本的适用性：静脉注射昂丹司琼 4-16mg 后，血浆中的测定浓度为 1.22-235.90ng/mL，而 CSF 中的浓度为 0.018-11.93ng/mL。总之，所开发的方法满足了所有验证要求，可用于评估人类 CNS 中昂丹司琼暴露的药代动力学研究。该方法具有基质体积小、校准范围广等优点，支持在预期进行丰富采样和多种药物剂量的研究中使用。
