Maher Hadir M, Alzoman Nourah Z, Shehata Shereen M
College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia; Faculty of Pharmacy, Department of Pharmaceutical Analytical Chemistry, University of Alexandria, El-Messalah, Alexandria 21521, Egypt.
College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.
J Pharm Biomed Anal. 2016 May 30;124:216-227. doi: 10.1016/j.jpba.2016.03.013. Epub 2016 Mar 5.
A sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry method has been developed and validated for the simultaneous analysis of selected tyrosine kinase inhibitors (TKIs)(gefitinib GEF, erlotinib ERL), corticosteroids (dexamethasone DEX, prednisolone PRED), and the antiemetic ondansetron (OND) in rat plasma samples. After the addition of domperidone (DOM) as internal standard (IS), spiked plasma samples were prepared using the solid phase extraction (SPE) C 18 cartridges. Chromatographic separation was performed on a Waters BEH C18 column with an isocratic elution using a mobile phase composed of acetonitrile and water, each with 0.1% formic acid, (80: 20, v/v), at a flow rate of 0.2 mL/min. Quantitation of the analytes was performed using the multiple reaction monitoring (MRM) mode with the positive ionization mode at m/z 447.25>128.08 (GEF), m/z 394.20>278.04 (ERL), m/z 393.30>147.04 (DEX), m/z 361.29>147.02 (PRED), m/z 294.18>170.16 (OND), and m/z 426.26>175.07 (DOM). The method was validated over the concentration range of 0.025-100 (GEF, ERL, OND) and 0.05-100 ng/mL plasma (PRED, DEX) with very low lower limit of quantification of 0.025 (GEF, ERL, OND) and 0.05 ng/mL (DEX, PRED). The intra- and inter-day precision (RSD%) evaluated at four different concentration levels were within the acceptable limits (<15%). The method provided good extraction recovery of all analytes from rat plasma (Er% from -14.05 to -1.08). The validated method was successfully applied to the pharmacokinetic studies following the oral administration of selected combinations of the studied drugs. This study can be readily applied in therapeutic drug monitoring (TDM) in patients receiving these drug combinations as well as investigation of possible drug interactions between TKIs and DEX/PRED/OND.
已开发并验证了一种灵敏且具选择性的超高效液相色谱 - 串联质谱法，用于同时分析大鼠血浆样本中的选定酪氨酸激酶抑制剂（TKIs）（吉非替尼GEF、厄洛替尼ERL）、皮质类固醇（地塞米松DEX、泼尼松龙PRED）以及止吐药昂丹司琼（OND）。加入多潘立酮（DOM）作为内标（IS）后，使用固相萃取（SPE）C18柱制备加标血浆样本。在Waters BEH C18柱上进行色谱分离，采用等度洗脱，流动相由乙腈和水组成，各含0.1%甲酸，比例为（80:20，v/v），流速为0.2 mL/min。使用多反应监测（MRM）模式，在正离子模式下对分析物进行定量，质荷比分别为m/z 447.25>128.08（GEF）、m/z 394.20>278.04（ERL）、m/z 393.30>147.04（DEX）、m/z 361.29>147.02（PRED）、m/z 294.18>170.16（OND）以及m/z 426.26>175.07（DOM）。该方法在0.025 - 100（GEF、ERL、OND）和0.05 - 100 ng/mL血浆（PRED、DEX）的浓度范围内得到验证，定量下限极低，分别为0.025（GEF、ERL、OND）和0.05 ng/mL（DEX、PRED）。在四个不同浓度水平评估的日内和日间精密度（RSD%）均在可接受范围内（<15%）。该方法从大鼠血浆中对所有分析物均提供了良好的提取回收率（提取率从 - 14.05至 - 1.08）。经验证的方法成功应用于所研究药物选定组合口服给药后的药代动力学研究。本研究可轻松应用于接受这些药物组合治疗的患者的治疗药物监测（TDM），以及TKIs与DEX/PRED/OND之间可能的药物相互作用研究。
