Early Evaluation And Study On Pharmacodynamics And Pharmacokinetics Of Hemay Series Compounds

Prodrugs is a new branch and more reconstruction in new drugs researcher. Theprincipal of prodrugs application is to change drugs physico-chemical property,improve pharmacokinetic characteristic of absorption, distribution,transport andmetabolism, increase bioavailability and selectivity of target site, depress side effectand toxicity, change dys-taste of drugs, and so on. The prodrugs can retain or improvethe effects of the parent drug, meanwhile, overcome the drawback of the parent drug.Prodrugs design is a way to pulsion new drugs.In recent years, it has been shown that thalidomide has the effect ofantiangiogenesis. It has been used to treat multiple myeloma in clinic, and treat othertumors in a phaseⅡtrial. Hemay series compounds （hemay014 and 015 ） are prodrugsof thalidomide. The early evaluation and study on pharmacodynamics andpharmacokinetics of hemay014, 015 was accumulated data in prophase research for newdrugs.The maximum inhibition rate of thalidomide on the proliferation of ECV-304 cellsby MTT assay in vitro was 43%. Compared to thalidomide, hemay014, and 015obviously inhibited the proliferation of ECV-304 cells in vitro, and the maximuminhibition rates were 100%, respectively. The IC₅₀ values of hemay014, 015 were 0.075μmol·ml^-1 and 0.143μmol·ml^-1, respectively. In tube formation assay in vitro,thalidomide, hemay014 and hemay015 at 0.195μmol·ml^-1 significantly inhibited tubeformation and exhibited broken tube connection structures formed by HUVEC atpresence of 20 ng·ml^-1 bFGE The effects of inhibition of hemay014, and 015 weresignificantly than thalidomide.Thalidomide, hemay014,015 could not inhibit the proliferation of tumor A549 cellline in vitro. The inhibitory rates of hemay014 of 40 mg·kg^-1 and hemay015 of 65mg·kg^-1 were 1.6% and 0.7% in nude mice bearing MX-1, respectively. The inhibitoryrate of Taxol of 4 mg·kg^-1 was 33.1%. Compared with alone application, hemay014,015respective combination with Taxol significantly inhibited the growth of subcutaneousxenograft of MX-1 in nude mice, the inhibitory rate was 58.4% and 74.3%, respectively. Hemay 014,015 could obviously increase the effect of Taxol on tumor inhibition.Compared with alone applied, drug toxicity was no significantly increased incombination applied.To establish a high performance liquid chromatography （HPLC） method fordeterming the active metabolite thalidomide of prodrug hemay014 and hemay015.Bothintra-day and inter-day precision were less than 10%, and the limit of detection was0.6ng. In the range of 0.2～20μg·ml^-1 of thalidomide, there was a linear relationshipwith a value for R²=0.9996. The mean recovery of thalidomide and internal in plasmawere 80% and 104.8%, respectively. Plasma sample could keep stability at roomtemperature for 6 h and at 4℃, -20℃for one week. The methodology could meet therequest of pharmacokinetics research.The disposition was conformed to a two compartment model after intravenousadministration of 5.9 mg·kg^-1 thalidomide. There were rare differences inpharmacokinetic parameters between male and female rats, the half time of distributionphase was 2.5～10 min, and ended after 10～45 min. The apparent volume ofdistribution was 0.76～1.06 L·kg^-1 and corresponded with water content body, indicatingthat thalidomide was distributed all over the body of rats. when the time of distributionphase was completed, the content of thalidomide of central compartment was equal withperipheral compartment. The half time of elimination phase (t_1/2β) was 159.8～165 min,and thalidomide was completely eliminated from body after 12～13 h administration,indicating that thalidomide was accumulated in the body of rats. The disposition wascomformed to a one compartment model after intragastric administration with 5.9mg·kg^-1 thalidomide; There were rare differences in pharmacokinetic parametersbetween male and female rats. The peak time of absorption was 100 min, indicating thatthalidomide was absorbed slowly from enteron in rats. The bioavailability was 10～24%, and the half time of elimination phase was 400～750 min that was 3-5 timeshigher than that of intravenous with thalidomide.Hemay 014 and 015 was not detected, and it was not found that the concentrationof thalidomide was elevated by sampling of one minute after intravenous administrationwith 10 mg·kg^-1 of hemay014 and 5.9 mg·kg^-1 of hemay015, indicating that the activemetabolite thalidomide can be transformed quickly after intravenous administrationwith hemay014 or hemay015. The fraction of metabolic transformation approximately was 0.59 and 0.66, respectively, indicating that the active metabolite thalidomide can betransformed completely after intravenous administration with hemay014 or hemay015.There were rare differences in pharmacokinetic parameter between thalidomide,hemay014 and hemay015, indicated that the pharmacokinetic characteristic ofthalidomide was not changed after a single intravenous administration with hemay014or hemay015.The disposition was conformed to a one compartment model after a singleintragastric administration with 5 mg·kg^-1、10 mg·kg^-1 or 20 mg·kg^-1 hemay014, therewere rare differences in pharmacokinetic parameters between male and female rats. Thepeak time of absorption was 35～100 min, indicating that hemay014 was absorbedslowly from enteron in rats, AUC, FX₀, and C_max of thalidomide increasedproportionally with the dosages. The bioavailability was 30～70%, and the half time ofelimination phase was 200～320 minThe disposition was conformed to a one compartment model after a singleintragastfic administration with 4.5 mg·kg^-1、9 mg·kg^-1 or 17.9 mg·kg^-1 hemay015, therewere rare differences in pharmacokinetic parameters between male and female rats. Thepeak time of absorption was 100～380 min, indicating that hemay015 was absorbedslowly from enteron in rats, AUC, FX₀, and C_max of thalidomide increasedproportionally with the dosages. The bioavailability was 40～80%, and the half time ofelimination phase was 200～250 minThere were differences in the comparison of pharmacokinetic parameters ofthalidomide between male and female after a single intragastric administration withidentical molar concentration of thalidomide, hemayO14 and hemay015:①the peaktime ofhemay015 was longer than hemay014 and thalidomide;②the absorption peakconcentration of hemay014 outclassed than hemay015 and thalidomide;③thebioavailability of hemay014 was 3 times of thalidomide, and the bioavailability ofhemay015 was larger a little than thalidomide. Compared with the kinetics ofthalidomide, the degree of absorption of hemay014 was obvious multiplication; thedegree of absorption of hemay015 had a little increased.To summarize, hemay series compounds should be further studied and developed...