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学科主题: 物理化学
题名: Ultra-performance liquid chromatographic-electrospray mass spectrometric determination of protocatechuic aldehyde glucuronidation in vitro
作者: Liu HX(刘慧鑫) ;  Yang L(杨凌)
会议名称: 16th North American Regional ISSX Meeting
会议日期: 2009-5-19
出版日期: 2009-05-19
会议地点: 美国
其他题名: 一种快速检测PALG的方法
通讯作者: 杨凌
部门归属: 十八室
主办者: 国际药代会
摘要: PAL has been considered as one of the major active constituents of Salvia miltiorrhiza, a commonly used traditional Chinese medicine for treating coronary heart disease, cerebrovascular disease and chronic renal failure. A number of pharmacological studies showed that PAL possessed arrays of biological activities as anti-cardium colic, reducing atherosclerosis and inhibiting the aggregation of platelets. However, detailed information on the metabolism of PAL and their pharmacokinetic fate in mammals are still scant. Drug metabolic profile plays an important role in discovering and developing the novel drug from the metabolites possessed the pharmacological activities. An understanding of the enzymology of the metabolic clearance of a drug, whether by phase I or phase II mechanisms, is pivotal to new drug development. Early knowledge of the potential biotransformations of drug in the target species is of great interest. In mammals, glucuronidation is a major conjugation reaction providing for metabolic elimination of exogenous compounds and endogenous compounds. This reaction is catalyzed by a family of enzymes known as UDP-glucuronosyltransferases (UGTs, EC 2.4.1.17). We have previously identified UGT1A6 was the major isoform responsible for PAL glucuronidation. Planar phenol derivatives like PAL, such as 4-methylumbelliferone and 4-nitrophenol, have been reported to be mainly conjugated by UGT1A6 isoform in mammals. However the contribution ratio differed extensively among the animal species. Therefore, an accurate and specific method for UGT activities toward PAL in mammalian tissues will be an important initial step in understanding the role of PAL glucuronidation pathway. Recently, UPLC was introduced as commercially available instrument, which has been applied for the pharmaceutical, toxicological and biochemical analysis. It has the advantages of the fast analysis, high peak capacity, good sensitivity and low consumption of samples. Furthermore, MS techniques play an important role in the metabolism study, because the high sensitivity of MS as an LC detector facilitates the detection of metabolites which are difficult to obtain by conventional means. In this study, a rapid and specific UPLC-MS method was developed for the determination of PAL glucuronidation activities in liver microsomes from different species. Liver microsomes incubation system with PAL resulted in the formation of two product peaks. Following the purification, the peaks were respectively confirmed as PAL meta-glucuronide (M1) and PAL para-glucuronide (M2) by MS and NMR. The method was validated for the determination of M1 and M2 with respect to specificity, linearity, detection limit, recovery, stability, precision and accuracy. The chromatographic separation was achieved on a UPLC BEH C18 column (50 mm × 2.1 mm i.d., 1.7 μm), with phase of acetonitrile-water (ratio 10:90). Selective ion reaction (SIR) monitor was specific for PAL, M1, M2 and I.S.. The method was linear over the concentration range 0.5-100 μM for M1 and M2 in spiked HLMs, respectively. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The method was successfully used to determine the kinetics of glucuronidation activities toward PAL in liver microsomes from different speices. The developed method was appropriated for rapid screening PAL glucuronidation activities in liver microsomes from different species.
语种: 中文
内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/113678
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Liu HX,Yang L. Ultra-performance liquid chromatographic-electrospray mass spectrometric determination of protocatechuic aldehyde glucuronidation in vitro[C]. 见:16th North American Regional ISSX Meeting. 美国. 2009-5-19.
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