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Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats.
- Source :
-
Malaria journal [Malar J] 2011 Oct 10; Vol. 10, pp. 293. Date of Electronic Publication: 2011 Oct 10. - Publication Year :
- 2011
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Abstract
- Background: Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats.<br />Methods: A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. In-situ permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC.<br />Results: For nominal doses increasing in a 1:2:4 proportion, the C(max) and AUC(0-∞) values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the C(max) and the AUC(0-t) values for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10(-5) cm/s) in permeability study.<br />Conclusions: The pharmacokinetic parameters of lumefantrine and its metabolite desbutyl-lumefantrine were successfully determined in rats for the first time. Lumefantrine displayed similar pharmacokinetics in the rat as in humans, with multiphasic disposition, low clearance, and a large volume of distribution resulting in a long terminal elimination half-life. The absolute oral bioavailability of lumefantrine was found to be dose dependent. Lumefantrine displayed high permeability in the in-situ permeability study.
- Subjects :
- Administration, Oral
Animals
Antimalarials administration & dosage
Biological Availability
Chromatography, High Pressure Liquid
Chromatography, Liquid
Ethanolamines administration & dosage
Fluorenes administration & dosage
Injections, Intravenous
Lumefantrine
Male
Metabolic Clearance Rate
Plasma chemistry
Rats
Tandem Mass Spectrometry
Antimalarials pharmacokinetics
Ethanolamines pharmacokinetics
Fluorenes pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1475-2875
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- Malaria journal
- Publication Type :
- Academic Journal
- Accession number :
- 21985153
- Full Text :
- https://doi.org/10.1186/1475-2875-10-293