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Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers
Author(s) -
Zhang ShuQiu,
Hai Trinh Ngoc,
Ilett Kenneth F.,
Huong Dinh Xuan,
Davis Timothy M. E.,
Ashton Michael
Publication year - 2001
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.0306-5251.2001.01461.x
Subject(s) - artemisinin , dihydroartemisinin , artesunate , medicine , pharmacology , pharmacokinetics , oral administration , artemisia annua , plasmodium falciparum , malaria , immunology
Aims 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.