右旋雷贝拉唑钠肠溶片在Beagle犬体内的药代动力学

目的：建立灵敏、快速的Beagle犬血浆中雷贝拉唑钠对映体及其代谢物的LC-MS/MS定量分析方法，并研究右旋雷贝拉唑钠肠溶片Beagle犬体内药代动力学特征。方法：以非那西丁为内标，血浆样品前处理以乙酸乙酯萃取，初始流动相为甲醇-水（5∶95），梯度洗脱，采用AGP 30713色谱柱分离，流速为0.5 mL·min^-1，进样量5.0 μL。通过电喷雾离子源，以多重反应监测模式（MRM）进行正离子检测。采用此法测定了Beagle犬口服右旋雷贝拉唑钠肠溶片10 mg 6 h后，雷贝拉唑钠对映体及其3种代谢物的血浆药物浓度。结果：犬血浆中雷贝拉唑对映体及其3种代谢产物的线性范围为2.0~2 000 ng·mL^-1，定量下限为2.0 ng·mL^-1，批内、批间精密度（RSD）介于1.2%~9.9%之间。Beagle犬单次口服右旋雷贝拉唑钠肠溶片后，血浆中未检测到雷贝拉唑钠左旋体，右旋雷贝拉唑钠、硫醚雷贝拉唑、雷贝拉唑砜及去甲基雷贝拉唑的AUC_（0-∞）分别为（1 486.82±956.68）、（265.03±182.16）、（79.60±45.92）、（220.10±119.90）μg·h·L^-1，T_max分别为（1.33±0.42）、（1.50±0.35）、（1.42±0.43）、（1.42±0.50）h，t_1/2分别为（0.35±0.12）、（1.34±1.07）、（0.43±0.07）、（0.43±0.20）h。结论：该方法可用于右旋雷贝拉唑钠肠溶片Beagle犬体内药代动力学研究，右旋雷贝拉唑钠在犬体内代谢迅速，未发现其转化为左旋体。

Objective: To establish a sensitive and rapid LC-MS/MS quantitative analysis method to simultaneously determine rabeprazole sodium enantiomers and their metabolites in Beagle dog plasma, and to study the pharmacokinetic characteristics of oral administration of (R)-rabeprazole sodium in vivo.Methods: The analytes and the internal standard phenacetin were extracted from plasma samples by ethyl acetate.The separation was accomplished in an AGP 30713 column, and the mobile phase consisted of methanol-water (5:95) by gradient elution at a flow rate of 0.5 mL·min^-1, sample volume 5 μL.The positive ion detection was carried out by the multiple reaction monitoring model (MRM) by the electrospray ion source.The plasma concentration of rabeprazole enantiomers and its 3 metabolites in beagle dogs were determined under these conditions within 6 h after the oral administration of enteric coated (R)-rabeprazole sodium 10 mg.Results: The linear range of the rabeprazole sodium enantiomer and its 3 metabolites in dog plasma was 2.0-2000 ng·mL^-1, the LOQ was 2.0 ng·mL^-1, the intra-batch and inter-batch precisions (RSDs) were between 1.2%-9.9%.The AUC_(0-∞) s of (R)-rabeprazole, rabeprazole thioether, rabeprazole sulfone and desmethyl rabeprazole in Beagle dogs after single oral administration of enteric coated (R)-rabeprazole sodium were (1486.82±956.68), (265.03±182.16), (79.60±45.92), (220.10±119.90)μg·h·L^-1, respectively.The T_maxS were (1.33±0.42), (1.50±0.35), (1.42±0.43), (1.42±0.50) h and the t_1/2s were (0.35±0.12), (1.34±1.07), (0.43±0.07), (0.43±0.20) h, respectively.No (S)-rabeprazole was detected.Conclusion: The established method is proved suitable for the pharmacokinetic study of (R)-rabeprazole sodium.The (R)-rabeprazole sodium and the metabolites can be quickly eliminated in the dog plasma but cannot be chiral biotransformed to (S)-rabeprazole.