| Artemisinin-based combination therapy(ACT)is the recommended treatment for uncomplicated Plasmodium falciparum malaria by World Health Organization(WHO).Compared to unaffordable modern antimalarial drugs,the available traditional antimalarial herb Artemisia annua L.(A.annua)is widely used in some developing nations for malarial prevention and treatment.Compared to the oral consumption of pure artemisinin,tea infusions and oral consumptions of dried leaves of A.annua can enhance both bioavailability and/or efficacy of QHS.Previous studies showed a synergistic potency of artemisinin in A.annua,while limited information is available on the component leading to enhanced antiplasmodial potency of artemisinin.In addition,the exact mechanism of this synergism remains unknown.This study was designed to investigate the component in A.annua extracts leading to enhanced antiplasmodial potency of QHS.The mechanism of the synergism was also studied based on drug metabolism.The effect of A.annua extracts on the metabolism/pharmacokinetics of artemisinin was evaluated.In addition,the synergistic component in A.annua extracts was screened based metabolic enzyme inhibition.The synergistic antiplasmodial potency of artemisinin either alone or in A.annua extracts was studied using both in vitro and in vivo techniques.1.Synergistic anti-plasmodial potency of artemisinin in Artemisia annua L.extracts via regulation of its metabolismThe metabolic/pharmacokinetic profiles of QHS and its three major phase I metabolites were investigated in healthy mice and rats after a single or multiple oral administrations of pure QHS or QHS in A.annua extracts.The antimalarial activity of QHS in the methanol A.annua extracts(MAE)against Plasmodium falciparum was studied in vitro(Plasmodium strain Pf3D7)and in vivo(rodent malaria Plasmodium yoelii).The recrudescence and survival time of infected mice were also recorded after drug treatment.Compared to pure artemisinin,a 2-6 fold increase in QHS exposure(AUC and Cmax)was found in healthy mice and rats after a single or multiple oral doses of MAE;however,metabolic biotransformation of QHS to its major metabolite monohydroxylated QHS(mediated by CYP3A),was both inhibited(a single dose)and induced(repeated doses)by MAE matrix.Compared to pure QHS(IC50 16.0 nM;ED50 6.8 mg/kg),in vivo tests showed synergic anti-plasmodial effect for QHS in MAE(ED50 1.9 mg/kg),while it was not observed in vitro(IC50 17.1 nM).These results support a synergistic anti-plasmodial potency of QHS in A.annua extracts,which was at least partly associated with increased exposure of QHS through absorption/metabolic enzyme regulation.Unfortunately,natural inducers of metabolic enzymes in A.annua may accelerate the rapid clearance of QHS after repeated administrations,and the synergism could not reduce the rate of recrudescence.2.Synergistic anti-plasmodial component of artemisinin in Artemisia annua L.extracts via enzyme inhibitionThree MAE fractions(MAE-Ⅰ,MAE-Ⅱ and MAE-Ⅲ)were prepared based on their polarity.The pharmacokinetic profiles of QIIS and its major phase I metabolite monohydroxylated artemisinin(M2)were investigated in healthy rats after a single oral administration of QMS in each MAE fraction.The antimalarial activity of QHS in each MAE fraction against Plasmodium falciparum was studied in vitro(Plasmodium strain Pf3D7)and in vivo(rodent malaria Plasmodium yoelii).Major components isolated from the target MAE fraction were evaluated for their enzyme inhibition.Compared to pure QHS,a 2-fold increase in QHS exposure(AUC and Cmax)was found in healthy rats after a single oral dose of QHS in the fraction MAE-III.In addition,metabolic biotransformation of QHS to the metabolite QHS-M(mediated by CYP3A)was inhibited by MAE-Ⅲ.Among nine major components isolated from MAE-Ⅲ(five sesquiterpenenes,three flavonoids and one phenolic acid),only arteannuin B(AB)showed an inhibition of CYP3A4(IC50 1.2 μM).3.The synergistic antiplasmodial effect between artemisinin and via metabolism regulationThe pharmacokinetic profiles of QHS and its major phase I metabolite monohydroxylated artemisinin(M2)were investigated in healthy mice after a single oral administration of QHS either in pure form or in combination with AB.The antimalarial activity of QHS in combination with AB against Plasmodium falciparum was studied in vivo(murine Plasmodium yoelii).The recrudescence and survival time of infected mice were also recorded after drug treatment.Compared to pure QHS,a 2-fold increase in QHS exposure(AUC and Cmax)was found in healthy mice after a single oral dose of QHS in combination with AB.In addition,metabolic biotransformation of QHS to the metabolite M2(mediated by CYP3A)was inhibited by AB.Compared to pure QHS,in vivo tests showed synergic anti-plasmodial effect for QHS in combination with AB.Unfortunately,the synergism cannot reduce the rate of recrudescence.These results support AB was one of main contributors in A.annua leading to enhanced antiplasmodial potency of QHS,which was at least partly associated with increased exposure of QHS through absorption/metabolic enzyme regulation. |
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