Abstract：Objective To analyze the tolerance and pharmacokinetics of Tefentai Tablets in healthy volunteers. Methods In this study,a randomized,double-blind method was used to study 26 healthy volunteers from January to June 2017,all patients were given 300 and 600 mg of Tefentanil,two doses of which were given single or multiple times,once a day for multiple times,7 days in a row,in which the drug elution cycle was 2 weeks.The pharmacokinetic parameters (the highest blood concentration [Cmax],the lowest blood concentration [Cmin],the average blood concentration[Cavg],the curve area of blood concentration over a period of time [AUC0-t],the infinite curve area of blood concentration[AUC0-∞] and accumulation index) were measured by high performance liquid chromatography at different time points.Pharmacokinetic parameters,high performance liquid chromatography characteristics and related adverse reactions were analyzed. Results The peak time (Tmax) was (1.02±0.13) h,and the half-life (t1/2) was (3.08±0.09) h after taking different doses of Tifentai Tablets for many times in healthy volunteers.The Tmaxof M8 was (3.05±0.07) h and t1/2was(9.56±0.67) h;The Tmaxof M9 was (4.11±0.15) h and T1/2was (6.17±0.21) h.At the dosage of 300 mg,there were no significant differences in Cmax,Cmin,Cavg,AUC0-t,AUC0-∞and accumulation index between multiple and single administration of Tifental (P>0.05).AUC0-tand AUC0-∞in multiple administration of metabolite N-benzoyl-O-(dimethylaminoethyl)-L-tyrosine (M8) and metabolite N-benzoyl-L-tyrosine-o-(N-oxidation-dimethylaminoethyl) - L-tyrosine(M9) were significantly higher than those of single administration (P<0.05).Cmaxof M9 multiple administration was higher than that of single administration,the difference was statistically significant (P<0.05).At the dosage of 600 mg,Cmaxin Tifental of multiple administration was higher than that of single administration,the difference was statistically significant (P<0.05).There were no significant differences in Cmin,Cavg,AUC0-t,AUC0-∞,accumulation index between multiple and single administration of Tifental (P>0.05).Cmaxand AUC0-tin multiple administration of M8 and M9 were significantly higher than that of single administration,the differences were statistically significant (P<0.05).The AUC0-∞of M9 multiple administration was higher than that of single administration,the difference was statistically significant (P<0.05).At the dose of 600 mg,repeated administration increased Cmax of Tifental,but had no significant effect on AUC0-∞of its exposure.The Cmaxof metabolites M8 and M9 increased,and the exposure of AUC0-∞increased.After several times of oral administration (doses of 300 and 600 mg) of Tifentai Tablets to healthy volunteers,a case of adverse event with foreign body sensation occurred in one volunteer at the dose of 600 mg,which was determined to be unrelated to the drug,and no volunteer withdrew from the trial due to adverse event. Conclusion Tifentai Tablets 600 mg dose not show obvious accumulation effect and high safety,in order to obtain better antiviral effect,it is suggested that the daily reference dose be 600 mg.
Meng FC，Xu WR，Li YZ，et al.In silico molecular docking study of repensine and bentysrepinine against HBV DNA polymerase[J].Chin Herb Med，2015，7（1）：39-44.
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