| Shexiang Baoxin Pill (SBP) is an important and widely used Chinesepatent medicine in treating coronary heart disease. As a classic and famousprescription for heat-clearing and detoxication, Huang-Lian-Jie-Du-Tang(HLJDT) has been widely used in the treatment of gastrointestinaldisorders, cardiovascular diseases and Alzheimer disease in clinical. Thethesis selected bufadienolides and ginsenosides as markers to investigatethe pharmacokinetic properties of SBP by liquidchromatography-electrospray ionization-tandem mass spectrometry(LC-ESI-MS/MS), while alkaloids and flavonoids as markers for thepharmacokinetic properties of HLJDT.Firstly, a LC-ESI-MS/MS method was established for thesimultaneous determination of resibufogenin, bufalin, gamabufotalin,telocinobufagin, arenobufagin, cinobufagin and bufotalin in rat plasma.The validated method was successfully applied to the pharmacokineticstudy of the seven bufadienolides in rat plasma after oral administration ofSBP. Concentration-time profiles of all the analytes presented typicalsingle-peak. They exhibited rapid absorption. All components except forcinobufagin eliminated quickly. The plasma concentration of bufalin wasthe highest due to its highest content in SBP, while the plasmaconcentration of bufatalin was the lowest due to its lowest content exceptfor telocinobufagin. However, in spite of the lower concentration oftelocinobufagin in SBP, its plasma concentration was not the lowestbecause of the metabolic transformation from bufalin. The results indictedpharmacokinetic properties of bufadienolides in SBP were subjected tochemical structures, contents for administration and the pharmacokinetic interaction of the prescribed chemical constituents.Secondly, a LC-ESI-MS/MS method was constructed for thesimultaneous determination of ginsenoside Rg1, ginsenoside Re,ginsenoside Rb3, ginsenoside Rc and ginsenoside Rb1in rat plasma. Thisfully validated method was successfully applied to the pharmacokineticstudy of the above five ginsenosides in rats after oral administration ofSBP with single-dose and multiple-dose. Pharmacokinetic parameters ofthe ppt-type ginsenosides (Rg1and Re) were remarkably different fromthose of the ppd-type ginsenosides (Rb3, Rc and Rb1). The plasma levelsof the ppd-type ginsenosides Rb3, Rc, and Rb1were significantly greaterwith slow elimination. The five ginsenosides shared rapid absorption.From the dose-exposure relationship, pharmacokinetics of all the analytesexhibited the nonlinear features. In the multiple-dose study, the plasmalevels of the ppt-type ginsenosides descreased remarkably, while those ofthe ppd-type ginsenosides did not change remarkably.Thirdly, a LC-ESI-MS/MS method has been developed and validatedfor simultaneous determination of eight active components includingwogonin, coptisine, berberine, palmatine, jatrorrhizine, phellodendrine,magnoflorine and wogonoside in rat plasma. This method was successfullyapplied to the pharmacokinetic study of the above eight compounds in ratsafter oral administration of HLJDT. All analytes except for magnoflorineexhibited multiple peaks phenomenon in plasma concentration curves.Magnoflorine presented remarkably different pharmacokinetic parameterscompared with the quaternary protoberberine-type alkaloids (coptisine,berberine, jatrorrhizine, phellodendrine and palmatine). The plasma levelsof the quaternary protoberberine-type alkaloids were consisted with thecorresponding compound contents from HLJDT.The results of this pharmacokinetic study provide a scientific basis forfurther exploring the active mechanism of SBP and HLJDT, revealing theirscientific connotation, and optimizing the clinical medication. |
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