P. Molunto

Pharmacokinetics and bioavailability of oral and intramuscular artemether

AbstractObjective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; tmax: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).

Simple high-performance liquid chromatographic method with electrochemical detection for the simultaneous determination of artesunate and dihydroartemisinin in biological fluids

A simple, rapid, sensitive, selective and reproducible high-performance liquid chromatographic method with reductive electrochemical detection is described for the simultaneous quantification of artesunate (ARS) and dihydroartemisinin (DHA) in plasma. The procedure involved the extraction of ARS, DHA and the internal standard (artemisinin, ARN) with a mixture of dichloromethane and tert.-methyl butyl ether (8:2, v/v). Chromatographic separation consisted of the mobile phase (acetonitrile-water containing 0.1 M acetic acid, pH 4.8; 45:55, v/v) running through the column (Nova-Pak C18, 150 cm x 3.9 mm I.D., 5 microm particle size). The retention times of alpha-DHA, beta-DHA, ARS and ARN were 2.9, 4.2, 4.5 and 6.0 min, respectively. The average recoveries of ARS, alpha-DHA and ARN in the concentration range of 10-800 ng/ml were 81.9, 88.2, 101.1 and 84.3%, respectively. The coefficients of variation (precision and repeatability) were below 10% for all three compounds at concentrations of 50, 200, 400 and 800 ng/ml, and below 20% at a concentration of 10 ng/ml. The limits of quantification for both ARS and alpha-DHA in spiked plasma samples were 5 and 3 ng/ml, respectively. The method was found to be suitable for application to pharmacokinetic studies of both ARS and DHA.

Disposition of oral quinine in acute falciparum malaria

SummaryPlasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l−1 compared to 5.7 mg·l−1 in convalescence.There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg−1·min−1, which was significantly lower than in convalescence — 2.67 ml·kg−·min−1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg−1·min−1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of α1 acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l−1 compared to 1.05 g·l−1 during convalescence.Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.

Determination of artemether and its major metabolite, dihydroartemisinin, in plasma using high-performance liquid chromatography with electrochemical detection

A rapid, selective, sensitive and reproducible HPLC with reductive electrochemical detection for quantitative determination of artemether (ART) and its plasma metabolite, dihydroartemisinin (DHA: alpha and beta isomers) in plasma is described. The procedure involved the extraction of ART, DHA and the internal standard, artemisinin (ARN) with dichloromethane-tert.-methylbutyl ether (1:1, v/v) or n-butyl chloride-ethyl acetate (9:1, v/v). Chromatographic separation was performed with a mobile phase of acetonitrile-water (20:80, v/v) containing 0.1 M acetic acid pH 5.0, running through a microBondapak CN column. The method was capable of separating the two isomeric forms of DHA (alpha, beta). The retention times of alpha-DHA, beta-DHA, ARN and ART were 4.6, 5.9, 7.9 and 9.6 min, respectively. Validation of the assay method was performed using both extraction systems. The two extraction systems produced comparable recoveries of the various analytes. The average recoveries of ART, DHA and ARN over the concentration range 80-640 ng/ml were 86-93%. The coefficients of variation were below 10% for all three drugs (ART, alpha-DHA, ARN). The minimum detectable concentrations for ART and alpha-DHA in spiked plasma samples were 5 and 3 ng/ml, respectively. The method was found to be suitable for use in clinical pharmacokinetic study.

The pharmacokinetic properties of intramuscular quinine in Gambian children with severe falciparum malaria.

Plasma quinine concentrations were measured in 21 Gambian children with severe falciparum malaria after intramuscular administration of a 20 mg (salt) per kg loading dose of quinine dihydrochloride followed by 10 mg/kg at 12 h intervals. Quinine was well absorbed reaching mean peak concentrations of 15.6 (standard deviation [SD] 4.5) mg/litre in a median time of 3 h (range 1-6 h). A one compartment model was fitted to the plasma concentration-time profile. The mean estimated systemic clearance (Cl/F) was 0.89 (SD 0.81) ml/kg/min and the mean elimination half life was 18.8 (SD 8.0) h. Two patients, one of whom died, had low plasma quinine levels which remained below 10 mg/litre. Mean peak and trough plasma concentrations after subsequent intramuscular doses ranged between 11.1 and 15.1 mg/litre. In most cases this dose regimen provided a satisfactory profile of blood concentrations for the treatment of severe malaria in children.

Pharmacokinetics of oral artemether in Thai patients with uncomplicated falciparum malaria.

Artemether has been demonstrated to be highly effective against multidrug resistant Plasmodium fulcipurum malaria [4]. Pharmacokinetic data of artemether available to date however, have been limited, particularly in patients with malaria. The aim of the present study was to investigate the absorptioddisposition kinetics of artemether and its active plasma metabolite dihydroartemisinin during acute and recovery phases of uncomplicated falciparum malaria.

Pharmacokinetics of quinine in patients with chronic renal failure

AbstractMethods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (tmax 4.5 vs 1.6 h, Cmax 6.17 vs 3.45 μg·ml−1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min−1·kg−1, whereas Vz/f remained unchanged (1.82 vs 2.78 1·kg−1). This resulted in the increased values of AUC and prolongation of the t1/2z and MRT in the patients (AUC 181.5 vs 61.8 μg·min−1·ml−1, t1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.