title: Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers.
abstract: OBJECTIVE
  To investigate whether coadministration of the antimalarials artesunate and artemisinin alters the clearance of either drug.
  
  
  METHODS
  Ten healthy Vietnamese males (Group AS) were randomized to receive a single dose of 100 mg oral artesunate (pro-drug of dihydroartemisinin) on day -5 and then once daily for 5 consecutive days (days 1-5). Oral artemisinin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Group AM) were given 500 mg oral artemisinin on day -5 and then further doses on days 1-5. Artesunate 100 mg was given on days 1 and 5. Artemisinin and dihydroartemisinin plasma concentrations on days -5, 1 and 5 were quantified by h.p.l.c. with on-line postcolumn derivatization and u.v. detection.
  
  
  RESULTS
  In Group AS, dihydroartemisinin oral clearance values (mean (95% CI)) were similar on day 1 (32 (22, 47)) l h(-1) and day 5 (38 (28, 51)) l h(-1) of daily artesunate administration but these mean values were approximately three fold higher compared with day -5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h(-1) on day 1-315 (241, 410) l h(-1) on day 5. In Group AM, dihydroartemisinin oral clearance on day 1 was 39 (34, 46) l h(-1) and increased 1.6 fold to 64 (48, 85) l h(-1) on day 5. In this group, artemisinin oral clearance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151, 285) l h(-1) on day -5-308 (257, 368) l h(-1) on day 1 and to 981 (678, 1420) l h(-1) on day 5. The increase in artemisinin oral clearance between days -5 and 1 (in the absence of artesunate) was similar to that between days 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisinin was not a significant metabolite of artemisinin.
  
  
  CONCLUSIONS
  Artesunate (dihydroartemisinin) did not alter the elimination of artemisinin. However, dihydroartemisinin elimination was inhibited by artemisinin. Artemisinin induced its own elimination even 5 days after a single oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Zhang
authors.forename: T N
authors.initials: TN
authors.lastname: Hai
authors.forename: K F
authors.initials: KF
authors.lastname: Ilett
authors.forename: D X
authors.initials: DX
authors.lastname: Huong
authors.forename: T M
authors.initials: TM
authors.lastname: Davis
authors.forename: M
authors.initials: M
authors.lastname: Ashton
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D037621:Artemisinins; D000077332:Artesunate; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate; C039060:artenimol; C031327:artemisinin