Study On Pharmacokinetic Characteristics Of Biguanide Marine Alkaloid FGFC1

With the changes in the pace of life and eating habits,cardiovascular and cerebrovascular diseases?CCVD?have become a common disease that seriously threatens human health,especially in middle-aged and elderly people over the age of 50.Disease rate,high mortality and high disability.Therefore,the development of drugs for the treatment of cardiovascular and cerebrovascular diseases has become the focus of research in the field of drug science research and development worldwide.Traditional thrombolytic drugs often have bleeding risks due to their side effects of thrombocytopenia,and the development of small molecules with safe thrombolytic pathways.Thrombolytic drugs have gradually become the consensus in the field of drug research and development.Based on the study of the pharmacokinetics of FGFC1 and the evaluation of its drug properties,the biotransformation characteristics of FGFC1 in vitro microsomal system were studied.The structure of FGFC1 transforming product PIO and its biotransformation were analyzed.process.The effective route of administration of FGFC1 and its excretion pathway were determined,which has application value in the development of safe and efficient small molecule thrombolytic drugs,and provides a theoretical basis for the use of FGFC1 as a new thrombolytic drug.The first chapter reviews the research status of domestic and foreign thrombolytic drugs and in vitro drug metabolism research methods,and introduces the CYP450enzyme subtypes in liver microsomes and their applications in drug metabolism research.In the second chapter,the biotransformation characteristics of the biguanide marine alkaloid FGFC1 in the in vitro liver microsome system and its transformation product PIO were studied.Liver microsomes were obtained from Wistar rats,and the increase and decrease of FGFC1 and its transformation products were detected by HPLC.The transformation products of FGFC1 were analyzed and identified by LC-MS/MS method.The phenotypic experiments were carried out to study the CYP450 enzyme system that catalyzes the biotransformation process.Subtype.The results showed that the in vitro metabolic half-life of FGFC1 was T_1/2=?96.25±2.3?min,and the intrinsic clearance rate was CL_int=?0.0720±0.0014?mL/?min·mg?.The only conversion product of FGFC1 is??2S,3S?-2-??E?-7,8-dihydroxy-4-methylnon-3-en-1-yl?-3,5,8-trihydroxy-2-methyl-3,4,8,9-tetrahydropyrano[2,3-e]isoindol-7?2H?-one??PIO?,its molecular mass spectrum and fragment peak?m/z?are 463.20[M+C₂H₃N+H]⁺and m/z 110.90[C₇H₈O+H+H]⁺?215.7[C₁₃H₂₆O₂+H]⁺?337.00[C₁₈H₂₇NO₅]⁺?337.00[C₂₅H₃₁NO₂]⁺.When the CYP3A4 subtype was inhibited,the transforming product PIO of FGFC1 was significantly different from the control group,which was reduced by 49.11%.The liver microsome CYP3A4 subtype enzyme system passed N-dealkylation reaction,N-oxidation reaction and hydrolysis reaction.Convert FGFC1 to PIOThe third chapter is to study the effect of different administration routes on the pharmacokinetic properties of FGFC1 in a rat model,and to determine the appropriate FGFC1 administration route.Rats were given intravenously and orally three different doses of FGFC1(1 mg·kg^-1,2.5 mg·kg^-1,and 5 mg·kg^-1),and blood was taken at different time points within 0-240 min.At the same time,the viscera was taken after intravenous injection in the high-dose group.The concentration of FGFC1 in the plasma and visceral samples was determined by HPLC and the pharmacokinetic parameters were calculated.The distribution of FGFC1 tissue under different routes of administration was observed.The results of pharmacokinetic experiments in the rat model showed that the in vivo elimination half-life(T_1/2)of FGFC1 intravenously and orally administered was?40.526±1.101?,?40.132±0.913?,?38.916±1.372?min and?20.687±0.717?,?19.829±0.336?,?19.913±1.004?min;peak concentration C_max?53.31±4.35?,?48.63±3.71?,?19.87±1.71??g·mL-1and?33.21±3.47?,?15.91±1.31?,?9.37±1.93??g·mL^-1;the total body elimination rate?CL?is?0.0055±0.0003?,?0.0043±0.0002?,?0.0044±0.0003?L·min^-1·kg^-1 and?0.0107±0.0004?,?0.0128±0.0004?,?0.0103±0.0002?L·min^-1·kg^-1;mean retention time?MRT?were?25.31±2.03?,?24.83±0.71?,?25.97±0.31?min and?19.74±0.87?,?18.94±0.45?,?19.31±0.77?min.FGFC1 prototypic drugs were observed in the liver,kidney,lung,stomach,large intestine,small intestine,and spleen,with the highest content in the liver,medium content in the kidney,lung,and stomach,and less in other organs.The results showed that FGFC1 showed poor pharmacokinetic characteristics after oral administration,and the absorption rate and absorption degree were low,and the pharmacokinetic characteristics exhibited by intravenous injection were better than oral administration.The way.FGFC1 can be distributed to all organs of the body after absorption,has good tissue distribution characteristics,and has good pharmacokinetic characteristics after intravenous injection,high absorption and long residence time in the body,and can exert good effects.In the fourth chapter,Rats were used as a model to inject 5 mg/kg FGFC1intravenously,and the cumulative excretion of FGFC1 and its transformation product PIO in urine,bile,and feces was measured by HPLC.The results showed that in the time range of 0-96 h,after 8-12 h of sampling,the cumulative excretion of FGFC1prototype drug was not observed in all metabolic pathways,and the FGFC1 prototype drug peaked at about 11 h,both lower than 0.7 mg/kg.At the same time,the FIOC1conversion product PIO was observed in various excretions,and the final cumulative excretion in bile,urine,and feces was?0.331±0.043?,?4.0377±0.118?,?0.177±0.004?mg/kg.The cumulative excretion of PIO in urine increased significantly with time,and its growth was no longer observed around 18h.The results showed that the transforming product PIO of FGFC1 in the liver microsome system was its excretion product,and the excretion of FGFC1 by the prototype drug form was small,and some untransformed prototype drugs were mainly excreted through bile.The main excretion pathway of FGFC1 is to be excreted through the urine after being converted into PIO,and has an effective excretion route.