右旋雷贝拉唑钠肠溶片在Beagle犬体内的药代动力学

Pharmacokinetic study of enteric coated (R)-rabeprazole sodium in Beagle dogs

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 m L·min^(-1),进样量5.0μL。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·m L^(-1),定量下限为2.0 ng·m L^(-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),Tmax分别为(1.33±0.42)、(1.50±0.35)、(1.42±0.43)、(1.42±0.50)h,t1/2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 m L·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 rabeprazo000 ng·m L^-1,the LOQ was 2.0 ng·m L-l1 e sodium enantiomer and its 3 metabolites in dog plasma was 2.0-2,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 Tmax S were（1.33±0.42）,（1.50±0.35）,（1.42±0.43）,（1.42±0.50）h and the t1/2 s 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.