Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay
1996; Wiley; Volume: 42; Issue: 5 Linguagem: Inglês
10.1111/j.1365-2125.1996.tb00054.x
ISSN1365-2125
AutoresPaktiya Teja‐Isavadharm, François Nosten, Dennis E. Kyle, C. Luxemburger, F. TER KUILE, James O. Peggins, Thomas G. Brewer, Nicholas J. White,
Tópico(s)Computational Drug Discovery Methods
ResumoBritish Journal of Clinical PharmacologyVolume 42, Issue 5 p. 599-604 Free Access Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay P. TEJA-ISAVADHARM, Corresponding Author P. TEJA-ISAVADHARM Department of Immunology and Parasitology, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, ThailandProfessor Nicholas J. White, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, ThailandSearch for more papers by this authorF. NOSTEN, F. NOSTEN Shoklo Malaria Research Unit, Mae Sod, Thailand Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, UKSearch for more papers by this authorD. E. KYLE, D. E. KYLE Department of Immunology and Parasitology, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington DC, USASearch for more papers by this authorC. LUXEMBURGER, C. LUXEMBURGER Shoklo Malaria Research Unit, Mae Sod, Thailand Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, ThailandSearch for more papers by this authorF. TER KUILE, F. TER KUILE Shoklo Malaria Research Unit, Mae Sod, ThailandSearch for more papers by this authorJ. O. PEGGINS, J. O. PEGGINS Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington DC, USASearch for more papers by this authorT. G. BREWER, T. G. BREWER Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington DC, USASearch for more papers by this authorN. J. WHITE, N. J. WHITE Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, UKSearch for more papers by this author P. TEJA-ISAVADHARM, Corresponding Author P. TEJA-ISAVADHARM Department of Immunology and Parasitology, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, ThailandProfessor Nicholas J. White, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, ThailandSearch for more papers by this authorF. NOSTEN, F. NOSTEN Shoklo Malaria Research Unit, Mae Sod, Thailand Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, UKSearch for more papers by this authorD. E. KYLE, D. E. KYLE Department of Immunology and Parasitology, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington DC, USASearch for more papers by this authorC. LUXEMBURGER, C. LUXEMBURGER Shoklo Malaria Research Unit, Mae Sod, Thailand Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, ThailandSearch for more papers by this authorF. TER KUILE, F. TER KUILE Shoklo Malaria Research Unit, Mae Sod, ThailandSearch for more papers by this authorJ. O. PEGGINS, J. O. PEGGINS Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington DC, USASearch for more papers by this authorT. G. BREWER, T. G. BREWER Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington DC, USASearch for more papers by this authorN. J. WHITE, N. J. WHITE Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, UKSearch for more papers by this author First published: November 1996 https://doi.org/10.1111/j.1365-2125.1996.tb00115.xCitations: 62AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract 1 The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg-1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.-ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA). 2 Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l-1 and for DHA of 1009 (639 to 1379) nmol l-1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half-life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.-ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3 Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC(0,6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4 These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible. References 1 Hien TT, White NJ. Qinghaosu. Lancet 1993; 341: 603– 608. 2 White NJ. Artemisinin: current status. Trans R Soc Trop Med Hyg 1994; 88 (Suppl 1): 3– 4. 3 Na Bangchang K, Karbwang J, Thomas CG, et al. Pharmacokinetics of artemether after oral administration to healthy Thai males and patients with acute uncomplicated falciparum malaria. Br J Clin Pharmacol 1994; 37: 249– 253. 4 Price RN, Nosten F, Luxemburger C, et al. Artesunate versus artemether in combination with mefloquine for the treatment of multidrug resistant falciparum malaria. Trans R Soc Trop Med Hyg 1995; 89: 523– 527. 5 Vinh H, Hien TT, Arnold K, Cuong BM, Phu NH. Treatment of cerebral malaria comparing artemisinin suppositories with IV artesunate and IV quinine. 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