Bat Ge Phenolic Alkali Human Pharmacokinetics And Science In Central Nervous System Drug Research

Objective:To investigate the pharmacokinetics of phenolic alkaloids of menispermum dauricum (PAMD) tablet after a single-dose oral administration to healthy volunteers and its general pharmacology.Method:The plasma concentrations of 12 healthy volunteers after oral single-dose PAMD (100mg,300mg,600mg) were measured by an LC-MS/MS method with protopine as the internal standard. Pharmacokinetic parameters were calculated, according to a self-control three-period cross-over investigation. Acute toxicity was observed in rats and mice after single-dose intragastric administration of PAMD. The medial lethal dose (LD50) and 95 % confidence of mice were calculated by Bliss's method. The effect of PAMD on general activities and condition, hypnotic synergy and coramine anti-convulsion activity were observed in mice.Results:1.The main pharmacokinetic parameters after oral single-dose of 100mg PAMD were as follows: Tmax1=1.08±0.25(h), Tmax2=4.17±0.94(h), Cmax1=12.30±3.26(ng.mL-1), Cmax2=6.26±1.53 (ng.mL-1), t1/2=3.57±1.28(h), AUC(0-t)=44.40±9.39(ng.h.mL-1), CL/F=1168±210(L.h-1), V/F=5922(L).The main pharmacokinetic parameters after oral single-dose of 300mg PAMD were as follows: Tmax1 =1.14±0.30(h), Tmax2 =4.25±0.97(h), Cmax1=33.60±12.50(ng.mL-1),Cmax2=16.90±4.17(ng.mL-1), t1/2= 2.87±0.86(h), AUC(0-t)=121±28.1 (ng.h.mL-1),CL/F= 1428±316(L.h-1), V/F=5891±1946(L).The main pharmacokinetic parameters after oral single-dose of 600mg PAMD were as follows: Tmax1=1.01±0.24(h), Tmax2= 4.08±0.67(h), Cmax1=69.80±24.50(ng.mL-1), Cmax2 =36.20±14.30(ng.mL-1), t1/2= 3.07±0.85(h), AUC(0-t) =243±76.7(ng.h.mL-1), CL/F=1474±440 (L.h-1),V/F =5592±2871(L).2.After single-dose intragastric administration of PAMD to mice, LD50 was 635 mg/kg and 95% confidence limit were 573～703 mg/kg. After single-dose intragastric administration of PAMD to rats, LD50 was greater than 3000 mg/kg. The PAMD was no effect on general activities and status in mice. No hypnotic synergy or anti-convulsant coramine effect were observed.Conclusion:1.The pharmacokinetic parameters(Tmax,Cmax,t1/2,AUC,CL/F,V/F ) after oral single-dose of PAMD were obtained to guide further clinical trials. AUC and Cmax was linear-correlated with the dose. C-T curves of the subjects'plasma samples showed the significant double-peak phenomenon, which may be related to drug gastrointestinal circulation.2.The results of acute toxicity study showed low toxicity of PAMD. After intragastric administration to mice, LD50 was 635 mg/kg and 95% confidence limit were 573～703 mg/kg. After intragastric administration of PAMD to rats, LD50 was greater than 3000 mg/kg.3.PAMD had no effect on general activities and status in mice. No hypnotic synergy or coramine anti-convulsant effect were observed in mice.