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沃诺拉赞焦谷氨酸盐在SD大鼠尿液排泄研究 被引量:1

Urine Excretion of Vonoprazan Pyroglutamate in SD Rats
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摘要 目的建立高效液相色谱-串联质谱测定沃诺拉赞焦谷氨酸盐在SD大鼠尿液中含量测定方法,并进行两药的尿液排泄对比研究。方法 API 4000质谱仪,采用电喷雾电离源(ESI),多反应监测(MRM)扫描分析,TAK-438 P和TAK-438 F的m/z 346.2→315.2,内标卡马西平:m/z 237.2→194。岛津LC-30液相色谱仪,色谱柱Agelient C18(4.6 mm×100 mm,3.5μm),流动相:甲醇-水(加入0.1%甲酸和10 mmol·L^(-1)乙酸铵)(60∶40),流速:0.6 m L·min^(-1),加预柱,进样5μL,洗脱6min,且对方法学进行验证均符合要求。分别进行等摩尔TAK-438 P及TAK-438 F在SD大鼠尿液排泄研究,测定24 h内原型药物的尿液累积排泄率。结果 TAK-438 P及TAK-438 F在24 h内原型药物的尿液累积排泄率分别为2.11%和2.03%,提示TAK-438 P及TAK-438 F原型药物尿液排泄比例不高,代谢可能是其主要的消除机制。结论高效液相色谱-串联质谱用于SD大鼠尿液中沃诺拉赞焦谷氨酸盐的含量测定,方法简便、快捷、灵敏度高;TAK-438 P主要经过代谢消除,且与TAK-438F累积排泄率无显著差异,为其成药性提供了依据。 OBJECTIVE To develop an LC-MS/MS method for the determination of vonoprazan pyroglutamate and vonoprazan fu marate in rat urine to determince the urine excretion of the two drugs in SD rats. METHODS The detection was performed on an API 4000 tandem mass spectrometer equipped with an electrospray ionization (ESI) source. Multiple reaction monitoring (MRM) was se lected with the transitions of m/z 346. 2 to 315.2 for TAK-438 P and m/z 237.2 to 194 for IS, respectively. Separation of the analytes was achieved by a Shimadzu liquid chromatography system with an Agelient C18 analytical column (4. 6 mm x 150 mm, 3.5 μm). Iso- cratic elution was adopted with mobile phase A ( 10 mmol · L - 1 ammonium acetate and 0. 1% formic acid) and mobile phase B ( meth- anol) at the ratio of 40: 60, at a flow rate of 0. 6 mL · min-l. The total run time was 6 rain and the injected sample volume was 5 μL. All the features of the developed method suggested it met the criteria for bioanalytieal methods recommended by regulatory authorities. The accumulative urine excretion rates of TAK-438 F and TAK-438 P were determined after oral administration of TAK-438 P and equi- molar TAK-438 F in SD rats. RESULTS The accumulative urine excretion rates of the prototype drugs were 2. 11% and 2. 03 % , re- spectively. The low excretion rates indicated that metabolism might be the major clearance mechanism of TAK-438 P and TAK-438 F. CONCLUSION This was the first time to establish and validate a simple, rapid and sensitive LC-MS/MS method for the quantifica- tion of TAK-438 P. There is no significant difference of the accumulative urine excretion rate between TAK-438 P and TAK-438 F in SD rats, which provides the basis for the druggability of TAK-438 P.
作者 乔元 黄剑林 王庆伟 梁佳龙 王力彬 井娟 QIAO Yuan;HUANG Jian-lin;WANG Qing-wei;LIANG Jia-long;WANG Li-bin;JING Juan(Department of Clinical pharmacy, Affiliated Hospital of Yan'an University, Yan'an, 716000, China;Department of Pharmacy, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China;Department of Medicinal Chemistry, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China)
出处 《中国药学杂志》 CAS CSCD 北大核心 2018年第12期1011-1017,共7页 Chinese Pharmaceutical Journal
关键词 沃诺拉赞焦谷氨酸盐 沃诺拉赞富马酸盐 高效液相色谱-串联质谱 尿液排泄 胃酸相关性疾病 vonoprazan pyroglutamate ( TAK-438 P) vonoprazan fumarate ( TAK-438 F) LC-MS/MS urine excretion acid-related diseases
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