Studies On The Biological Activity And Pharmacokinetics And Metabolism Of Pseudo-ginsenoside GQ

Pseudo-ginsenoside GQ(PGQ)is a new ginsenoside of ocotillol-type structure.It's a perspective compound with treatment and prevention of cardiovascular and cerebrovascular diseases bioactivity.In order to accelerate the development of PGQ,and provide a new drug with exact efficacy,small toxicity,low-cost,controlled quality for the large number of patients with myocardial ischemia.In this paper,the physical and chemical nature of PGQ and the activity of myocardial ischemia were further studied.The pharmacokinetics characters of PGQ were studied systematically for the first time.Specific experimental results are summarized as follows:1.In-depth study on the physical and chemical properties of PGQ.PGQ were synthesized with a rate of 4%by hydrolysis and oxidation cyclization from the total saponin of the stems and leaves of ginseng.PGQ's purity was 99.2%.It was insoluble in water,soluble in ethanol, 1,4-dioxane ring,very slightly soluble 1,2-propylene glycol,soluble in methanol.[α]D²⁰=+26.7°(c=1.00,MeOH).Liebermann-Burchard and Molish reactions were all positive.The structure of PGQ was identified by elemental analysis,MS,X-ray single crystal diffraction,NMR(¹³CNMR,¹HNMR,HMQC,HMBC, ¹H-¹HCOSY,etc.).The molecular formula was C₄₂H₇₂O₁₄·H₂O,molecular weight was 819.01.X-ray single crystal diffraction results identified C20.C24 were S configuration.The structure of the PGQ is 3-O-[β-D-glucopyranosyl-(1-2)-β-D-glucopyranosyl]-dammar-20S,24S-epoxy-3β,12β,25-triol, named pseudo-ginsenoside GQ(PGQ).2.Cardiac hemodynamics on the normal Wistar rats in vitro were studied. The PGQ role and mechanism of anti-myocardial ischemia ware revealed for the first time.Three dose of PGQ(0.0375g·L^-1,0.075g·L^-1,and 0.15g·L^-1) could slow HR and showed a negative effect of frequency.It significant decrease effects on Ap,LVSP and±dp/dt and negative inotropic effect showed dose dependent.Its bioactivity intensity and mechanism of anti-myocardial ischemia were similar to verapamil.In vitro studies on ex vivo hearts of Wistar rats showed that PGQ could antagonize the positive inotropic effect which was induced by Ca²⁺ concentration increased.PGQ could reduced the Iso-inducedβreceptor activation.3.PGQ's pharmacokinetics actions in Wistar rats and Beagle dogs were revealed for the first time.The contents of PGQ were detected using high performance liquid chromatographic method(HPLC)with evaporative light scattering detector(ELSD).Ginsenoside Rb1 was selected as the internal standard quantitative,biological samples were dealed with Strata C18-solid-liquid extraction to reduce the interference of other ingredients.The method was validated to achieve the satisfactory precision and recovery,and the results were accurate and reproducible.Beagle dogs were administrated PGQ(2.0mg·kg^-1,4.0mg·kg^-1and 8.0 mg·kg^-1)intravenously.The plasma concentration-time curves were charted with "3P97" medicine Kinetics and fitting procedures.The results showed that the pharmacokinetic model was 2 chamber model.Dose of high, medium and low group was linear with AUC.There was no significant change in t_1/2β.The linear range was 2.0 to 8.0mg·kg^-1in Beagle dogs. Wistar rats were administrated PGQ(3.0 mg·kg^-1,12.0 mg·kg^-1,48.0 mg·kg^-1)by sublingual intravenous.Plasma concentration-time curves were charted by the "3P97" pharmacokinetics fitting procedures.The results showed that the pharmacokinetic model was 2 chamber model too.Dose was linear with AUC in three groups,there was no significant change in t_1/2β.There was in a linear dynamic characteristics within 3.0 to 48.0 mg·kg^-1in rats.4.The organism distribution of PGQ was studied in rats for the first time.Wistar rats were administrated PGQ through sublingua intravenous. PGQ were detected in the small intestine,lung,heart,stomach,uterus,fat, kidney,spleen after administration 10min.A little PGQ was detected in the brain,muscle,liver,testicular.PGQ in ovarian could not be detected.The results showed that:PGQ mainly distributed in the small intestine,lung,heart, kidney,stomach,fat.and its concentration was the highest in small intestine.The protein binding rate were for the first time detected in rats and human plasma.The results showed that the protein binding rate was 70%to 78%.It was similar in rats and human.5.The excretion of PGQ was studied in Wistar rats for the first time. The excretion of renal,biliary and fecal were studied mainly in this paper.Rats were administrated by sublingual intravenous with PGQ(12 mg·kg^-1).Bile.urine and fecal excretion were studied.The contents of PGQ were detected at different times.In bile,PGQ content in 0-1h was to maximum.It was gradually decline within 3h.But it was increased during 3 to 5h.This may be due to PGQ being absorded into blood in different parts of the intestine.In fecal excretion of PGQ,the content was the highest in 4 to 8h.There was no PGQ could not be detected after 24h.In urine,PGQ could be detected only in the 0 to 4h.PGQ was mainly excreted in bile 42.06%,secondly in fecal(10.01%).There were prototype drug in the bile,urine and fecal. In this paper,the study results of PGQ provided important theoretical basis for further R & D,design and optimization of clinical treatment.