Alpha 1‐acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum malaria.

Silamut, Kamolrat; Molunto, P.; Ho, May; Davis, Timothy M. E.; White, Nicholas J.

doi:10.1111/j.1365-2125.1991.tb03904.x

Cited by 79 publications

(47 citation statements)

References 25 publications

(32 reference statements)

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“…The reduction in AUC probably results from expansion in the apparent volume of distribution and improved systemic clearance on recovery with increased presystemic (first-pass), intestinal, and hepatic metabolism. In patients with acute malaria the apparent volume of distribution of protein-bound basic drugs, such as quinine and presumably the artemisinin derivatives, is reduced as a consequence of increased binding to ␣-1-acid glycoprotein (11,18). It is not clear whether hepatic artesunate and DHA metabolism is autoinduced, as has been described for artemisinin itself (1,9).…”

Section: Vol 44 2000mentioning

confidence: 93%

“…1 Factory; Guangxi, People's Republic of China) were crushed, dissolved in water to provide the weight-adjusted dose (within Ϯ2.5 mg), and immediately given to the patient. Blood samples were taken through an indwelling catheter in a forearm vein at 0, 5, 15, 30, 45, 60, 90, and 120 min and then at 3,4,6,8,12,18, and 24 h following drug administration. A second dose of artesunate (2 mg/kg) was then given by the opposite route, i.e., if oral administration was given first, then intravenous administration was given second.…”

Section: Methodsmentioning

confidence: 99%

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Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

Newton

Suputtamongkol

Teja‐Isavadharm

et al. 2000

Antimicrob Agents Chemother

136

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The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunateassociated antimalarial activity.Artemisinin (qinghaosu) and its derivatives are a major advance in antimalarial treatment (8). These drugs are increasingly used in southeast Asia for the treatment of multidrugresistant Plasmodium falciparum malaria (2,8,15,22). Artesunate, the most widely available of the artemisinin-related compounds, is a hemisuccinate derivative of dihydroartemisinin (DHA). It may be given parenterally, intravenously, intramuscularly, orally, or rectally. Oral artesunate is used either alone or in combination, usually with mefloquine (15). Despite considerable use in areas where malaria is endemic, there are relatively few data on the pharmacokinetics of artesunate in the treatment of malaria (2-4, 6, 9, 13, 21, 27). There are concerns that the various artesunate formulations may have different bioavailabilities and that the development of resistance will be accelerated if suboptimal doses are used (13,24). Optimization of dosing recommendations is also important because of evidence that high doses of parenteral artemisinin derivatives (artemether, arteether) are neurotoxic in experimental mammals (16).Oral artesunate and artemether, but not artemisinin, are hydrolyzed rapidly back to the common metabolite DHA, which is intrinsically more active as an antimalarial agent. Oral artesunate may be considered mainly a prodrug for DHA, as the metabolite is the main contributor to overall antimalarial activity (2, 6). Thus, in order to compare different formulations of these drugs accurately and to guide the accurate choice of compound, the bioavailability of the antimalarial agent must be assessed.Chemical methods for the assay of DHA and the related derivatives have a limit of accurate quantitation above the range of concentrations which provide significant antimalarial effect. High-performance liquid chromatography (HPLC) with electrochemical detect...

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Section: Vol 44 2000mentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

Newton

Suputtamongkol

Teja‐Isavadharm

et al. 2000

Antimicrob Agents Chemother

136

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“…14,15 Data are lacking on whether reduced artemisinin clearance is related to ␣-1-acid glycoprotein binding or to decreased metabolic conversion. Decreased metabolic conversion of arteether to DHA in rat liver microsomes was seen in malaria-infected rodents, but hepatic conversion to DHA was not affected by disease in the isolated perfused rat liver model.…”

Section: Discussionmentioning

confidence: 99%

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

Teja‐Isavadharm¹,

Watt²,

Eamsila³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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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.

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“…A likely explanation for the increase in bioavailability of dihydroartemisinin in malaria patients compared with healthy subjects is a decrease in hepatic clearance of dihydroartemisinin due to malaria (1). Alpha-acid glycoprotein levels also increase during acute malaria (16), and similar to quinine, this may cause an increase in binding of the protein-bound dihydroartemisinin, with a reduction in the apparent volume of distribution of the drug (12).…”

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confidence: 99%

Pharmacokinetics and Ex Vivo Pharmacodynamic Antimalarial Activity of Dihydroartemisinin-Piperaquine in Patients with Uncomplicated Falciparum Malaria in Vietnam

Nguyen¹,

Nguyen²,

Nguyen³

et al. 2009

Antimicrob Agents Chemother

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Compared to healthy subjects, malaria patients show a reduction in the mean oral clearance (1.19 versus 5.87 liters/h/kg of body weight) and apparent volume of distribution (1.47 versus 8.02 liters/kg) of dihydroartemisinin in Vietnamese patients following treatment with dihydroartemisinin-piperaquine (Artekin) for uncomplicated Plasmodium falciparum. Dihydroartemisinin is responsible for most of the ex vivo antimalarial activity of dihydroartemisinin-piperaquine.

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Alpha 1‐acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum malaria.

Cited by 79 publications

References 25 publications

Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

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

Pharmacokinetics and Ex Vivo Pharmacodynamic Antimalarial Activity of Dihydroartemisinin-Piperaquine in Patients with Uncomplicated Falciparum Malaria in Vietnam

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