Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria.

Abstract

Abstract. The single-dose pharmacokinetics of 100 mg of orally administered artesunate (AS) were studied in 6 patient volunteers with uncomplicated falciparum malaria and in 6 healthy volunteers. Plasma concentrations of both the parent drug, AS, and its major metabolite, dihydroartemisinin (DHA), were measured simultaneously by highperformance liquid chromatography (HPLC) with electrochemical detection (ECD). The antimalarial activity of each plasma sample measured by an in vitro bioassay (BA) was used to derive activity concentrations. Artesunate was absorbed rapidly and then almost completely hydrolyzed to DHA in patients, whereas hydrolysis was incomplete in healthy volunteers. The mean Ϯ standard deviation (SD) maximum concentration (C max ) of AS was 296 Ϯ 110 nmol/ L, the time to peak blood level (t max ) was 0.71 Ϯ 0.66 hr, the half-life (t 1/2,z ) was 0.41 Ϯ 0.34 hr, and the bioavailability over 12 hr (area under the curve [AUC] (0-12) ) was 253 Ϯ 185 nmol hr/L. Measured by HPLC, the C max and AUC (0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) values of DHA in patients with malaria were significantly greater than in volunteers (1,948 Ϯ 772 and 1,192 Ϯ 315 nmol/L; 4,024 Ϯ 1,585 and 1,763 Ϯ 607 nmol hr/L, respectively; P Յ 0.05). These differences were even greater when measured by BA. The C max for patients with malaria was 2,894 Ϯ 2,497 and 795 Ϯ 455 nmol/L for volunteers, and AUC (0-12) was 5,970 Ϯ 3,625 and 1,307 Ϯ 391 nmol hr/L, respectively (P Յ 0.05). In contrast, DHA parameter estimates for t 1/2,z and t max were similar between patients and healthy volunteers, with values of 0.80 Ϯ 0.30 versus 0.87 Ϯ 0.06 hr and 1.50 Ϯ 0.55 versus 1.13 Ϯ 0.52 hr, respectively (P Ͼ 0.5). Both drug metabolism and tissue protein binding could contribute to the differences between the antimalarial activity of artemisinin drugs in healthy volunteers and malaria infected patients.

Pharmacokinetics of Artesunate Alone and in Combination with Sulfadoxine/Pyrimethamine in Healthy Sudanese Volunteers

“…35 Moreover, after AS alone, the median value of the V d of DHA in our study was 4.9 L/kg, which is also consistent with the value of 4.14 L/kg in the previous report. 35 Furthermore, after AS alone, the median value of t 1/2 for DHA in our study was 1.6 hours and was comparable to the values reported in previous studies with healthy volunteers (1.5-1.68 hours). [35][36][37] The lack of effect of SP on the pharmacokinetic parameters of AS and DHA could be caused by the difference in metabolic pathways of AS and SP.…”

“…35 Furthermore, after AS alone, the median value of t 1/2 for DHA in our study was 1.6 hours and was comparable to the values reported in previous studies with healthy volunteers (1.5-1.68 hours). [35][36][37] The lack of effect of SP on the pharmacokinetic parameters of AS and DHA could be caused by the difference in metabolic pathways of AS and SP. In this regard, AS is known to be completely hydrolyzed in the blood by tissue cholinesterases to yield its active metabolite, DHA, 38 and DHA is further conjugated by the UDP-glucuronosyltransferase system.…”

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…The present study investigated the metabolomics of serum from asthma mice, and evaluated potential restorative effects of artesunate in BALF and serum metabolome of allergic asthma in comparison with dexamethasone. We presented the first kinetic study of artesunate in mice showing rapid conversion to DHA, the major active metabolite (Teja-Isavadharm et al 2001;Morris et al 2011), within 1 h after i.p. administration.…”

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

“…These include the area under the concentration-time curve (2-to 26-fold) [43,[46][47][48], the peak concentrations of DHA in plasma (2-to 54-fold) [43,44,[46][47][48], and the clearance/bioavailability for DHA (2-to 22-fold) [43,46,48,49]. Large interindividual variations in the pharmacokinetics of DHA have also been seen in healthy Southeast Asian and Caucasian subjects [50][51][52][53]. The basis for such a large inter-individual pharmacokinetic variability observed in these studies [43,44,[46][47][48][49] may include drug metabolism polymorphisms.…”