title: Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice.
abstract: BACKGROUND
  The Chinese have used Artemisia annua as a tea infusion to treat fever for >2000 years. The active component is artemisinin. Previously we showed that when compared to mice fed an equal amount of pure artemisinin, a single oral dose of dried leaves of Artemisia annua (pACT) delivered to Plasmodium chabaudi-infected mice reduced parasitemia at least fivefold. Dried leaves also delivered >40 times more artemisinin in the blood with no toxicity. The pharmacokinetics (PK) of artemisinin delivered from dried plant material has not been adequately studied.
  
  
  METHODS
  Healthy and Plasmodium chabaudi-infected mice were oral gavaged with pACT to deliver a 100 mg kg(-1) body weight dose of artemisinin. Concentrations of serum artemisinin and one of its liver metabolites, deoxyartemisinin, were measured over two hours by GCMS.
  
  
  RESULTS
  The first order elimination rate constant for artemisinin in pACT-treated healthy mice was estimated to be 0.80 h(-1) with an elimination half-life (T½) of 51.6 min. The first order absorption rate constant was estimated at 1.39 h(-1). Cmax and Tmax were 4.33 mg L(-1) and 60 min, respectively. The area under the curve (AUC) was 299.5 mg min L(-1). In contrast, the AUC for pACT-treated infected mice was significantly greater at 435.6 mg min L(-1). Metabolism of artemisinin to deoxyartemisinin was suppressed in infected mice over the period of observation. Serum levels of artemisinin in the infected mice continued to rise over the 120 min of the study period, and as a result, the T½ was not determined; the Cmax and Tmax were estimated at ≥6.64 mgL(-1) and ≥120 min, respectively. Groups of healthy mice were also fed either artemisinin or artemisinin mixed in mouse chow. When compared at 60 min, artemisinin was undetectable in the serum of mice fed 100 mg AN kg(-1) body weight. When plant material was present either as mouse chow or Artemisia annua pACT, artemisinin levels in the serum rose to 2.44 and 4.32 mg L(-1), respectively, indicating that the presence of the plant matrix, even that of mouse chow, had a positive impact on the appearance of artemisinin in the blood.
  
  
  CONCLUSIONS
  These results showed that artemisinin and one of its drug metabolites were processed differently in healthy and infected mice. The results have implications for possible therapeutic use of pACT in treating malaria and other artemisinin-susceptible diseases.
authors.affiliation: Department of Biology and Biotechnology, Worcester Polytechnic Institute, 100 Institute Rd, Worcester, MA 01609, United States. Electronic address: weathers@wpi.edu.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Weathers
authors.affiliation: Laboratory of Medical Zoology, Department of Microbiology, University of Massachusetts, Amherst, MA 01003, United States.
authors.forename: Mostafa A
authors.initials: MA
authors.lastname: Elfawal
authors.affiliation: Department of Biology and Biotechnology, Worcester Polytechnic Institute, 100 Institute Rd, Worcester, MA 01609, United States.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Towler
authors.affiliation: School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences (MCPHS University), Worcester, MA 01608, United States.
authors.forename: George K
authors.initials: GK
authors.lastname: Acquaah-Mensah
authors.affiliation: Laboratory of Medical Zoology, Department of Microbiology, University of Massachusetts, Amherst, MA 01003, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Rich
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics*; D031172:Artemisia annua; D037621:Artemisinins / Q000097:blood / Q000493:pharmacokinetics*; D008288:Malaria / Q000097:blood / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018515:Plant Leaves; D016788:Plasmodium chabaudi
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C055261:deoxyartemisinin; C031327:artemisinin
keywords: Artemisia annua; Artemisinin; Deoxyartemisinin; Malaria; Plasmodium chabaudi; pACT