不同剂量注射用泮托拉唑钠在犬体内药代动力学研究

Pharmacokinetic study of different doses of pantoprazole sodium injections in dogs

关键词:  泮托拉唑钠  超高效液相色谱-串联质谱联用  药动学  线性关系分析

Key words:  Pantoprazole sodium  LC-MS/MS  Pharmacokinetics  Linear relationship analysis

摘要:

为研究不同剂量的泮托拉唑钠在犬体内的药代动力学特征,建立LC-MS/MS法测定犬血浆中泮托拉唑钠浓度的分析方法。血浆样品采用乙腈沉淀蛋白处理后,采用Waters ACQUITY BEH C18(2.1 mm×50 mm,1.7 μm)色谱柱进行分离,以乙腈-水(含0.1％的甲酸)为流动相进行梯度洗脱,在电喷雾正离子模式下,采用多反应监测模式进行定性与定量分析。应用此方法测定静脉注射给予低(2.00 mg/kg)、中(4.00 mg/kg)、高(8.00 mg/kg)三个剂量后犬体内泮托拉 唑钠的血药浓度,并使用Phoenix WinNonlin软件计算主要的药动学参数。结果显示：泮托拉唑钠在15.0~15000 ng/mL浓度范围内呈现良好线性关系(R2^＞0.999),定量限为15.0 ng/mL；方法的批内与批间精密度均小于15.0%,准确度RE%在9.00%以内；方法提取回收率在95.0%~101%范围内。比格犬静脉注射三个剂量组(2.00 mg/kg、4.00 mg/kg、8.00 mg/kg)后的主要药代参数如下:AUC0-t 分别为7714±2256 h.ng/mL、14389±5039 h.ng/mL、41149±9193 h.ng/mL；AUC0-∞分别为7748±2248 h.ng/mL、14445±5042 h.ng/mL、41250±9232 h.ng/mL；C0分别为8312±2460 ng/mL、16135±7401ng/mL、37969±16618 ng/mL；t1/2分别为0.638±0.0899 h、0.625±0.185 h、0.783±0.151 h,剂量变化对t1/2、V无明显影响(P>0.05)。结果表明,建立的方法简单、高效、灵敏,静脉注射不同剂量后,注射用泮托拉唑钠在犬体内代谢较快,符合线性药代动力学特征。

Abstract:

I n order to research the pharmacokinetics of pantoprazole sodium( Pan-Na) at different doses in dogs, an analytical method was established for the determination of pantoprazole sodium concentration in dog plasma by LC-MS/MS . Plasma samples were effectively extracted by acetonitrile while diclofenac sodium was used as internal standard. Separation was achieved on a Waters ACQUITY BEH C18 (50mm?2.1mm, 1.7μm) column using acetonitrile-0.1% formic acid in water as the mobile phase. Under the electrospray positive ion mode, the multi-reaction monitoring mode was used for qualitative and quantitative analysis of pantoprazole. The plasma concentration of pantoprazole sodium in dogs was determined by this method after intravenous administration of three groups: low (2.00 mg/kg), medium (4.00 mg/kg) and high (8.00 mg/kg)，and the main pharmacokinetic parameters were calculated by Phoenix WinNonlin software. The results indicated that pantoprazole sodium had a good linear relationship in the concentration range of 15.0~15000 ng/mL(R2?0.999)and the lower limit of quantification was 15.0 ng/m L. The intra- and inter-batch precisions (RSD )were both less than 15.0%, the accuracy RE% was within 9.00% and the recovery was between 95.0%~101% The main pharmacokinetic parameters after intravenous injection of the three dose groups(2.00 mg/kg,4.00 mg/kg and 8.00 mg/kg) in beagle dogs were as follows:AUC0-t was 7714±2256 h·ng/mL，14389±5039 h·ng/mL and 41149±9193 h·ng/mL；AUC0-∞was7748±2248 h·ng/mL，14445±5042 h·ng/mL and41250±9232 h·ng/mL；C0 was8312±2460 ng/mL，16135±7401ng/mL and37969±16618 ng/mL；t1/2 was 0.638±0.0899 h，0.625±0.185 h and0.783±0.151 h. The dose change had no significant effect on t1/2 and V (P>0.05). The results showed that the established method was simple, efficient and sensitive, the pantoprazole sodium had a faster metabolism and met the linear pharmacokinetic characteristics in dogs after intravenous injection of different dosages .